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BACKGROUND: Interstitial lung diseases (ILDs) include a large number of diseases associated with progressive pulmonary fibrosis (PPF), including idiopathic pulmonary fibrosis (IPF). Despite the rarity of each of the fibrotic ILDs individually, they cumulatively affect a considerable number of patients. PPF is characterised by an excessive collagen deposition leading to functional decline. OBJECTIVES: Therapeutic options are limited to nintedanib and pirfenidone which are only able to reduce fibrosis progression. CD206-expressing M2 macrophages are involved in fibrosis progression, and whether they may be relevant therapeutic targets or biomarkers remains an open question. RESULTS: In our study, CD206+ lung macrophages were monitored in bleomycin-induced lung fibrosis in mice by combining flow cytometry, scRNAseq and in vivo molecular imaging using a single photon emission computed tomography (SPECT) radiopharmaceutical, 99mTc-tilmanocept. The antifibrotic effect of the inhibition of M2 macrophage polarisation with a JAK inhibitor, tofacitinib, was assessed in vivo. We demonstrate that CD206-targeted in vivo SPECT imaging with 99mTc-tilmanocept was able to accurately detect and quantify the increase in CD206+ macrophages from early to advanced stages of experimental fibrosis and ex vivo in lung biopsies from patients with IPF. CD206-targeted imaging also specifically detected a decrease in CD206+ lung macrophages on nintedanib and tofacitinib treatment. Importantly, early in vivo imaging of CD206+ macrophages allowed the prediction of experimental lung fibrosis progression as well as nintedanib and tofacitinib efficacy. CONCLUSIONS: These findings indicate that M2 macrophages may be relevant theranostic targets for personalised medicine for patients with PPF.
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PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor outcome and limited therapeutic options. Imaging of IPF is limited to high-resolution computed tomography (HRCT) which is often not sufficient for a definite diagnosis and has a limited impact on therapeutic decision and patient management. Hypoxia of the lung is a significant feature of IPF but its role on disease progression remains elusive. Thus, the aim of our study was to evaluate hypoxia imaging with [18F]FMISO as a predictive biomarker of disease progression and therapy efficacy in preclinical models of lung fibrosis in comparison with [18F]FDG. METHODS: Eight-week-old C57/BL6 mice received an intratracheal administration of bleomycin (BLM) at day (D) 0 to initiate lung fibrosis. Mice received pirfenidone (300 mg/kg) or nintedanib (60 mg/kg) by daily gavage from D9 to D23. Mice underwent successive PET/CT imaging at several stages of the disease (baseline, D8/D9, D15/D16, D22/D23) with [18F]FDG and [18F]FMISO. Histological determination of the lung expression of HIF-1α and GLUT-1 was performed at D23. RESULTS: We demonstrate that mean lung density on CT as well as [18F]FDG and [18F]FMISO uptakes are upregulated in established lung fibrosis (1.4-, 2.6- and 3.2-fold increase respectively). At early stages, lung areas with [18F]FMISO uptake are still appearing normal on CT scans and correspond to areas which will deteriorate towards fibrotic lesions at later timepoints. Nintedanib and pirfenidone dramatically and rapidly decreased mean lung density on CT as well as [18F]FDG and [18F]FMISO lung uptakes (pirfenidone: 1.2-, 2.9- and 2.6-fold decrease; nintedanib: 1.2-, 2.3- and 2.5-fold decrease respectively). Early [18F]FMISO lung uptake was correlated with aggressive disease progression and better nintedanib efficacy. CONCLUSION: [18F]FMISO PET imaging is a promising tool to early detect and monitor lung fibrosis progression and therapy efficacy.
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Fluordesoxiglucose F18 , Fibrose Pulmonar Idiopática , Animais , Biomarcadores , Progressão da Doença , Humanos , Hipóxia , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Fibrose Pulmonar Idiopática/tratamento farmacológico , Camundongos , Misonidazol/análogos & derivados , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons , Compostos RadiofarmacêuticosRESUMO
BACKGROUND: We report here a case where no everolimus pleural diffusion was evidenced at the same time of pleural progression of a metastatic breast cancer treated with everolimus and exemestane. CASE DESCRIPTION: A 69-year-old woman was diagnosed in October 2006 with stage III invasive ductal breast adenocarcinoma. After nine months of everolimus and exemestane treatment, she presented with a pleural progression. Everolimus concentration was measured in blood and in pleural fluid. Residual blood concentration was at 9.1 ng/mL, while no everolimus was observed in the pleural fluid. MANAGEMENT AND OUTCOME: Due to inefficacy of everolimus in this patient, she was switched to palbociclib and fulvestrant. CONCLUSION: Everolimus seems to have a poor diffusion in the pleural fluid.
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Neoplasias da Mama/tratamento farmacológico , Everolimo/farmacocinética , Idoso , Androstadienos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Progressão da Doença , Everolimo/administração & dosagem , Feminino , Humanos , Piperazinas/administração & dosagem , Piridinas/administração & dosagemRESUMO
Interstitial lung diseases (ILDs) include a large number of diseases and causes with variable outcomes often associated with progressive fibrosis. Although each of the individual fibrosing ILDs are rare, collectively, they affect a considerable number of patients, representing a significant burden of disease. Idiopathic pulmonary fibrosis (IPF) is the typical chronic fibrosing ILD associated with progressive decline in lung. Other fibrosing ILDs are often associated with connective tissues diseases, including rheumatoid arthritis-ILD (RA-ILD) and systemic sclerosis-associated ILD (SSc-ILD), or environmental/drug exposure. Given the vast number of progressive fibrosing ILDs and the disparities in clinical patterns and disease features, the course of these diseases is heterogeneous and cannot accurately be predicted for an individual patient. As a consequence, the discovery of novel biomarkers for these types of diseases is a major clinical challenge. Heat shock proteins (HSPs) are molecular chaperons that have been extensively described to be involved in fibrogenesis. Their extracellular forms (eHSPs) have been recently and successfully used as therapeutic targets or circulating biomarkers in cancer. The current review will describe the role of eHSPs in fibrosing ILDs, highlighting the importance of these particular stress proteins to develop new therapeutic strategies and discover potential biomarkers in these diseases.
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Biomarcadores/metabolismo , Proteínas de Choque Térmico/antagonistas & inibidores , Fibrose Pulmonar Idiopática/tratamento farmacológico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Animais , Progressão da Doença , Proteínas de Choque Térmico/metabolismo , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Doenças Pulmonares Intersticiais/metabolismo , Doenças Pulmonares Intersticiais/patologia , Terapia de Alvo MolecularRESUMO
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterised by myofibroblast proliferation and abnormal extracellular matrix accumulation in the lungs. Transforming growth factor (TGF)-ß1 initiates key profibrotic signalling involving the SMAD pathway and the small heat shock protein B5 (HSPB5). Tripartite motif-containing 33 (TRIM33) has been reported to negatively regulate TGF-ß/SMAD signalling, but its role in fibrogenesis remains unknown. The objective of this study was to elucidate the role of TRIM33 in IPF. METHODS: TRIM33 expression was assessed in the lungs of IPF patients and rodent fibrosis models. Bone marrow-derived macrophages (BMDM), primary lung fibroblasts and 3D lung tissue slices were isolated from Trim33-floxed mice and cultured with TGF-ß1 or bleomycin (BLM). Trim33 expression was then suppressed by adenovirus Cre recombinase (AdCre). Pulmonary fibrosis was evaluated in haematopoietic-specific Trim33 knockout mice and in Trim33-floxed mice that received AdCre and BLM intratracheally. RESULTS: TRIM33 was overexpressed in alveolar macrophages and fibroblasts in IPF patients and rodent fibrotic lungs. Trim33 inhibition in BMDM increased TGF-ß1 secretion upon BLM treatment. Haematopoietic-specific Trim33 knockout sensitised mice to BLM-induced fibrosis. In primary lung fibroblasts and 3D lung tissue slices, Trim33 deficiency increased expression of genes downstream of TGF-ß1. In mice, AdCre-Trim33 inhibition worsened BLM-induced fibrosis. In vitro, HSPB5 was able to bind directly to TRIM33, thereby diminishing its protein level and TRIM33/SMAD4 interaction. CONCLUSION: Our results demonstrate a key role of TRIM33 as a negative regulator of lung fibrosis. Since TRIM33 directly associates with HSPB5, which impairs its activity, inhibitors of TRIM33/HSPB5 interaction may be of interest in the treatment of IPF.
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Fibrose Pulmonar Idiopática , Fator de Crescimento Transformador beta1 , Animais , Bleomicina/toxicidade , Modelos Animais de Doenças , Fibroblastos , Humanos , Pulmão , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Fatores de TranscriçãoRESUMO
PURPOSE OF REVIEW: Pulmonary fibrosis is a chronic and progressive lung disease involving unclear pathological mechanisms. The present review presents and discusses the major and recent advances in our knowledge of the pathogenesis of lung fibrosis. RECENT FINDINGS: The past months have deepened our understanding on the cellular actors of fibrosis with a better characterization of the abnormal lung epithelial cells observed during lung fibrosis. Better insight has been gained into fibroblast biology and the role of immune cells during fibrosis. Mechanistically, senescence appears as a key driver of the fibrotic process. Extracellular vesicles have been discovered as participating in the impaired cellular cross-talk during fibrosis and deeper understanding has been made on developmental signaling in lung fibrosis. SUMMARY: This review emphasizes the contribution of different cell types and mechanisms during pulmonary fibrosis, highlights new insights for identification of potential therapeutic strategies, and underlines where future research is needed to answer remaining open questions.
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Fibroblastos/fisiologia , Doenças Pulmonares Intersticiais/complicações , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/fisiopatologia , Comunicação Celular , Senescência Celular , Matriz Extracelular , Vesículas Extracelulares/fisiologia , Humanos , Pulmão/patologia , Fibrose Pulmonar/imunologia , Mucosa Respiratória , Transdução de SinaisRESUMO
BACKGROUND: Idiopathic and toxic pulmonary fibrosis are severe diseases starting classically in the subpleural area of the lung. It has recently been suggested that pleural mesothelial cells acquire a myofibroblast phenotype under fibrotic conditions induced by TGF-ß1 or bleomycin. The importance and role of inflammation in fibrogenesis are still controversial. In this work, we explored the role of IL-1ß/caspase-1 signaling in bleomycin lung toxicity and in pleural mesothelial cell transformation. METHODS: C57BL/6 mice were intravenously injected with either bleomycin or nigericin or NaCl as control. In vitro, the Met5A cell line was used as a model of human pleural mesothelial cells. RESULTS: Intravenous injections of bleomycin induced lung fibrosis with histologically-proven peripheral distribution, collagen accumulation in the pleural and subpleural area, and overexpression of markers of myofibroblast transformation of pleural cells which migrated into the lung. These events were associated with an inflammatory process with an increase in neutrophil recruitment in pleural lavage fluid and increased caspase-1 activity. TGF-ß1 was also overexpressed in pleural lavage fluid and was produced by pleural cells following intravenous bleomycin. In this model, local pleural inhibition of IL-1ß with the IL-1ß inhibitor anakinra diminished TGF-ß1 and collagen accumulation. In vitro, caspase-1 inhibition interfered with Met5A cell transformation into the myofibroblast-like phenotype induced by bleomycin or TGF-ß1. Moreover, nigericin, a caspase-1 activator, triggered transformation of Met5A cells and its intra-pleural delivery induced fibrogenesis in mice. CONCLUSIONS: We demonstrated, after intravenous bleomycin injection in mice, the role of the pleura and highlighted the key role of IL-1ß/caspase-1 axis in this fibrogenesis process.
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Anti-Inflamatórios/farmacologia , Bleomicina , Caspase 1/metabolismo , Inibidores de Caspase/farmacologia , Fibrose Pulmonar Idiopática/prevenção & controle , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-1beta/antagonistas & inibidores , Pulmão/efeitos dos fármacos , Pleura/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular , Citoproteção , Modelos Animais de Doenças , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/enzimologia , Fibrose Pulmonar Idiopática/patologia , Interleucina-1beta/metabolismo , Pulmão/enzimologia , Pulmão/patologia , Camundongos Endogâmicos C57BL , Nigericina/farmacologia , Pleura/enzimologia , Pleura/patologia , Fatores de Tempo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Nirmatrelvir/ritonavir is a protease inhibitor antiviral drug indicated in the treatment of severe acute respiratory syndrome coronavirus-2 infections in high-risk patients for a severe disease. Unfortunately, ritonavir, used to boost nirmatrelvir pharmacokinetics, can also inhibit or induce the metabolism of other co-administered drugs substrates. This may lead to a subsequent risk of adverse drug reaction and lack of efficacy. In this study, we aimed at describing the expert advices provided by the biological pharmacology network of the SFPT (i.e., the therapeutic drug monitoring specialists working in the laboratories of the pharmacology departments in France/Belgium). From February to August 2022, we collected all specialized advices provided by the biological pharmacology network of the SFPT. Seven pharmacology departments actively participated in the study (Brussels Saint-Luc Hospital in Belgium, Caen, Dijon, Nantes, Nancy, Rennes and Toulouse in France). We collected the following data: patient's age, date of nirmatrelvir/ritonavir initiation, clinical department requiring the expert advice, patient's treatments, and advice provided. One hundred and six expert advice on 753 drugs were provided during the seven months of data collection. Two centers provided 83% of all the expert advice (around 8/month). Patients originated form a transplantation department in 65% of the cases. The most common request were for cardiac drugs (28%), immunosuppressive drugs (24%) and endocrine drugs (18%). The advice were distributed as follows: treatment continuation, treatment discontinuation during the antiviral course, dosage adjustment, and treatment switch in 59%, 28%, 11%, and 1.6% of the cases, respectively. Only 2 pieces of advice (0.3%) constituted treatment contra-indications. Drug monitoring was proposed in 10% of prescription lines. Expert advice provided by the biological pharmacology network of the SFPT allows securing the combination of nirmatrelvir/ritonavir with other concomitant drugs. Most of eligible patients to the antiviral drug can benefit from it despite the risk of drug-drug interaction.
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BACKGROUND AND OBJECTIVE: Trough abiraterone concentration (ABI Cmin) of 8.4 ng/mL has been identified as an appropriate efficacy threshold in patients treated for metastatic castration-resistant prostate cancer (mCRPC). The aim of the phase II OPTIMABI study was to evaluate the efficacy of pharmacokinetics (PK)-guided dose escalation of abiraterone acetate (AA) in underexposed patients with mCRPC with early tumour progression. METHODS: This multicentre, non-randomised study consisted of two sequential steps. In step 1, all patients started treatment with 1000 mg of AA once daily. Abiraterone Cmin was measured 22-26 h after the last dose intake each month during the first 12 weeks of treatment. In step 2, underexposed patients (Cmin < 8.4 ng/mL) with tumour progression within the first 6 months of treatment were enrolled and received AA 1000 mg twice daily. The primary endpoint was the rate of non-progression at 12 weeks after the dose doubling. During step 1, adherence to ABI treatment was assessed using the Girerd self-reported questionnaire. A post-hoc analysis of pharmacokinetic (PK) data was conducted using Bayesian estimation of Cmin from samples collected outside the sampling guidelines (22-26 h). RESULTS: In the intention-to-treat analysis (ITT), 81 patients were included in step 1. In all, 21 (26%) patients were underexposed in step 1, and 8 of them (38%) experienced tumour progression within the first 6 months. A total of 71 patients (88%) completed the Girerd self-reported questionnaire. Of the patients, 62% had a score of 0, and 38% had a score of 1 or 2 (minimal compliance failure), without a significant difference in mean ABI Cmin in the two groups. Four patients were enrolled in step 2, and all reached the exposure target (Cmin > 8.4 ng/mL) after doubling the dose, but none met the primary endpoint. In the post-hoc analysis of PK data, 32 patients (39%) were underexposed, and ABI Cmin was independently associated with worse progression-free survival [hazard ratio (HR) 2.50, 95% confidence interval (CI) 1.07-5.81; p = 0.03], in contrast to the ITT analysis. CONCLUSION: The ITT and per-protocol analyses showed no statistical association between ABI underexposure and an increased risk of early tumour progression in patients with mCRPC, while the Bayesian estimator showed an association. However, other strategies than dose escalation at the time of progression need to be evaluated. Treatment adherence appeared to be uniformly good in the present study. Finally, the use of a Bayesian approach to recover samples collected outside the predefined blood collection time window could benefit the conduct of clinical trials based on drug monitoring. OPTIMABI trial is registered as National Clinical Trial number NCT03458247, with the EudraCT number 2017-000560-15).
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Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/patologia , Idoso , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Progressão da Doença , Relação Dose-Resposta a Droga , Androstenos/administração & dosagem , Androstenos/farmacocinética , Androstenos/uso terapêutico , Acetato de Abiraterona/administração & dosagem , Acetato de Abiraterona/farmacocinética , Acetato de Abiraterona/uso terapêutico , Antineoplásicos/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Antineoplásicos/sangue , Metástase NeoplásicaRESUMO
Reorganization of myometrial extracellular matrix (ECM) is essential for the uterus to achieve powerful synchronous contractions during labor. Remodeling of the ECM has been implicated in membrane rupture and cervical ripening. Because maternal obesity is associated with both delivery disorders and elevated circulating leptin levels, this study aimed to assess the ability of leptin to interfere with lipopolysaccharide (LPS)-induced myometrial ECM remodeling. Myometrial biopsy samples were obtained from women undergoing cesarean delivery before labor onset. Myometrial explants were incubated for 48 h with LPS and leptin. LPS challenge was associated with a marked decrease in collagen content and in heat shock protein (HSP) 47 expression, reflecting a disruption in collagen synthesis and an increase in matrix metalloproteinase (MMP) 2 and MMP9 activity and in MMP2, MMP9, and MMP13 expression. Leptin prevented an LPS-induced decrease in myometrial collagen content in a concentration-dependent manner. This effect was associated with an increase in HSP47 expression and a decrease in MMP2 and MMP9 activity and expression. These results show that leptin prevents LPS-induced myometrial remodeling through collagen synthesis stimulation and inhibition of MMP2 and MMP9. Our study strengthens the hypothesis that leptin plays a role in the development of obesity-related delivery disorders.
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Matriz Extracelular/metabolismo , Inflamação/metabolismo , Leptina/farmacologia , Lipopolissacarídeos/farmacologia , Miométrio/efeitos dos fármacos , Miométrio/metabolismo , Adulto , Biópsia , Colágeno/metabolismo , Relação Dose-Resposta a Droga , Matriz Extracelular/patologia , Feminino , Proteínas de Choque Térmico HSP47/metabolismo , Humanos , Técnicas In Vitro , Inflamação/patologia , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Miométrio/patologia , Obesidade/metabolismo , Obesidade/patologia , Gravidez , Complicações na Gravidez/metabolismo , Complicações na Gravidez/patologiaRESUMO
INTRODUCTION: Thiopental is a thiobarbiturate given in the case of brain injuries to reduce intracranial pressure and to manage cerebral ischemia. A pharmacokinetic model has been described previously in critically ill patients with a different therapeutic strategy. New treatment options prompted us to investigate if drug-drug interactions occur. A new model is proposed describing the influence of concomitant administration of esomeprazole on the distribution of thiopental. METHOD: The study population comprised 52 critically ill patients (body weight 47.1-114 kg) aged 18-78 years who had been admitted into the critical care unit for treatment of intracranial hypertension. A total mean dose of 282.8 ± 172.7 mg/kg was given in 96 ± 72 h. Pharmacokinetic analysis was performed by using a nonlinear mixed-effect population model. RESULT: A one-compartment open model with first-order elimination identified two covariates, namely, body weight on clearance and volume of distribution, and the administration of esomeprazole on volume of distribution. The mean values (% relative standard error) for total clearance (CL) and for central volume of distribution (Vd) in patients with and without concomitant esomeprazole were 5.3 L/h (9.2 %) and 256.1 (6.4 %) and 153.2 l (19.2 %), respectively. CONCLUSION: Based on these results, we conclude that concomitant administration of esomeprazole increases the volume of distribution and the half-live of thiopental. This drug-drug interaction should be considered when a target concentration has to be reached.
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Antiulcerosos/administração & dosagem , Esomeprazol/administração & dosagem , Hipnóticos e Sedativos/farmacocinética , Modelos Biológicos , Inibidores da Bomba de Prótons/administração & dosagem , Tiopental/farmacocinética , Adolescente , Adulto , Idoso , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/metabolismo , Lesões Encefálicas/fisiopatologia , Estado Terminal , Interações Medicamentosas , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/sangue , Masculino , Pessoa de Meia-Idade , Tiopental/administração & dosagem , Tiopental/sangue , Adulto JovemRESUMO
Idiopathic pulmonary fibrosis is a chronic, progressive and lethal disease of unknown etiology that ranks among the most frequent interstitial lung diseases. Idiopathic pulmonary fibrosis is characterized by dysregulated healing mechanisms that lead to the accumulation of large amounts of collagen in the lung tissue that disrupts the alveolar architecture. The two currently available treatments, nintedanib and pirfenidone, are only able to slow down the disease without being curative. We demonstrated in the past that HSPB5, a low molecular weight heat shock protein, was involved in the development of fibrosis and therefore was a potential therapeutic target. Here, we have explored whether NCI-41356, a chemical inhibitor of HSPB5, can limit the development of pulmonary fibrosis. In vivo, we used a mouse model in which fibrosis was induced by intratracheal injection of bleomycin. Mice were treated with NaCl or NCI-41356 (six times intravenously or three times intratracheally). Fibrosis was evaluated by collagen quantification, immunofluorescence and TGF-ß gene expression. In vitro, we studied the specific role of NCI-41356 on the chaperone function of HSPB5 and the inhibitory properties of NCI-41356 on HSPB5 interaction with its partner SMAD4 during fibrosis. TGF-ß1 signaling was evaluated by immunofluorescence and Western Blot in epithelial cells treated with TGF-ß1 with or without NCI-41356. In vivo, NCI-41356 reduced the accumulation of collagen, the expression of TGF-ß1 and pro-fibrotic markers (PAI-1, α-SMA). In vitro, NCI-41356 decreased the interaction between HSPB5 and SMAD4 and thus modulated the SMAD4 canonical nuclear translocation involved in TGF-ß1 signaling, which may explain NCI-41356 anti-fibrotic properties. In this study, we determined that inhibition of HSPB5 by NCI-41356 could limit pulmonary fibrosis in mice by limiting the synthesis of collagen and pro-fibrotic markers. At the molecular level, this outcome may be explained by the effect of NCI-41356 inhibiting HSPB5/SMAD4 interaction, thus modulating SMAD4 and TGF-ß1 signaling. Further investigations are needed to determine whether these results can be transposed to humans.
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Everolimus has proven efficacy for prevention of rejection in adult de novo renal and cardiac transplant recipient in combination with ciclosporine and corticosteroids. Therapeutic drug monitoring (TDM) with target trough concentration (C0) value from 3 to 8 µg/L has been proposed. Through a systematic review of the literature, this work explored a level of recommendation for this TDM. Everolimus exhibits both wide interindividual pharmacokinetic variability and poor relationship between dose and exposure. A good relationship has been reported between C0 values and global exposure to the drug (i.e. AUC). Although C0 > 3 µg/L has been associated with a decreased incidence of rejection, the upper limit of 8 µg/L has never been formally validated. No clinical trial testing other exposure indices or comparing efficacy and/or toxicity of everolimus therapy with and without TDM has been published so far. Consequently the level of recommendation for everolimus monitoring is "recommended".
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Monitoramento de Medicamentos/métodos , Rejeição de Enxerto/prevenção & controle , Imunossupressores/uso terapêutico , Sirolimo/análogos & derivados , Relação Dose-Resposta a Droga , Everolimo , Medicina Baseada em Evidências , Transplante de Coração/métodos , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/economia , Imunossupressores/farmacocinética , Transplante de Rim/métodos , Sirolimo/efeitos adversos , Sirolimo/economia , Sirolimo/farmacocinética , Sirolimo/uso terapêuticoRESUMO
Everolimus has proven efficacy for prevention of rejection in adult de novo renal and cardiac transplant recipient in combination with ciclosporine and corticosteroids. Therapeutic drug monitoring (TDM) with target trough concentration (C0) value from 3 to 8 µg/L has been proposed. Through a systematic review of the literature, this work explored a level of recommendation for this TDM. Everolimus exhibits both wide interindividual pharmacokinetic variability and poor relationship between dose and exposure. A good relationship has been reported between C0 values and global exposure to the drug (i.e. AUC). Although C0 > 3 µg/L has been associated with a decreased incidence of rejection, the upper limit of 8 µg/L has never been formally validated. No clinical trial testing other exposure indices or comparing efficacy and/or toxicity of everolimus therapy with and without TDM has been published so far. Consequently the level of recommendation for everolimus monitoring is "recommended".
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We compared the apoptotic mechanism involved in U937 human monocytic cell line in presence of oxidized low-density lipoproteins (oxLDL) obtained after treatment with hypochlorous acid (HOCl) or copper (Cu). Both types of oxLDL induced U937 apoptotic cell death via the mitochondrial pathway. In contrast to HOCl-oxLDL, Cu-oxLDL induced apoptosis via a caspase-independent mechanism, with no activation of pro-caspase-3, but via the release of apoptosis inducing factor (AIF) from mitochondria. The apoptotic program of the monocyte differs depending on the mode of LDL oxidation, based on differences in the oxidatively modified components of the two oxLDL types.
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Apoptose , Lipoproteínas LDL/metabolismo , Mitocôndrias/metabolismo , Monócitos/fisiologia , Fator de Indução de Apoptose/metabolismo , Cobre/farmacologia , Humanos , Ácido Hipocloroso/farmacologia , Lipoproteínas LDL/farmacologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Oxirredução , Células U937RESUMO
In order to limit 5-fluorouracil (5-FU) toxicity, some health agencies recommend evaluating dihydropyrimidine dehydrogenase (DPD) deficiency before any 5-FU treatment introduction. In our study, we investigated relationships between 5-FU clearance and markers of DPD activity such as uracilemia (U), dihydrouracilemia (UH2)/U ratio, or genotype of the gene encoding DPD (DPYD). All patients with gastrointestinal cancers who received 5-FU-based regimens form March 2018 to June 2020 were included in our study. They routinely benefited of a pre-therapeutic DPYD genotyping and phenotyping. During 5-FU infusion, blood samples were collected to measure 5-FU steady-state concentration in order to adapt 5-FU doses at the following cycles. A total of 169 patients were included. Median age was 68 (40-88) years and main primary tumor sites were colorectal (40.8%) and pancreas (31.4%), metastatic in 76.3%. 5-FU was given as part of FOLFIRINOX (44.4%), simplified FOLFOX-6 (26.6%), or docetaxel/FOLFOX-4 (10.6%). Regarding DPD activity, median U and UH2/U were, respectively, 10.8 ng/mL and 10.1, and almost 15% harbored a heterozygous mutation. On the range of measured U and UH2/U, no correlation was observed with 5-FU clearance. Moreover, in patients with U < 16 ng/mL, 5-FU exposure was higher than in other patients, and most of them benefited of dose increase following 5-FU therapeutic drug monitoring (TDM). If recent guidelines recommend decreasing 5-FU dose in patients harboring U ≥ 16 ng/mL, our study highlights that those patients are at risk of under-exposure and that 5-FU TDM should be conducted in order to avoid loss of efficacy.
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This study investigated the influence of an eicosapentaenoic acid (EPA)- or a docosahexaenoic acid (DHA)-supplemented diet on the deleterious effects of lysophosphatidylcholine (LPC) on endothelium-dependent vasorelaxation of Golden Syrian hamster thoracic aorta. In a second step, LPC-modulated phospholipase A(2) (PLA(2))-derived ways of relaxation were investigated. Golden Syrian hamsters were fed for 6 weeks with a control diet or an EPA- or DHA-supplemented diet. Aortic fatty acid composition was analyzed by gas chromatography. Aortic rings were incubated for 20 minutes with LPC before constructing cumulative concentration-response curves for acetylcholine (ACh; 3 nmol/L-30 micromol/L) or sodium nitroprusside (3 nmol/L-30 micromol/L). The EPA- or DHA-supplemented diet increased n-3 polyunsaturated fatty acids in aortic fatty acids content because of the increase of EPA or DHA content, respectively, and decreased arachidonic acid aortic content. Lysophosphatidylcholine (1, 10, 15, and 20 micromol/L) induced a concentration-dependent inhibition of ACh-induced relaxation of preconstricted aortic rings in the control group, but did not influence sodium nitroprusside-induced aortic relaxation. The DHA- or EPA-supplemented diet worsened LPC (20 micromol/L) inhibitory effects on ACh-induced vasorelaxation. In the control diet group, ACh-induced relaxation was abolished by the nitric oxide synthase inhibitor (l-N(G)-nitro-arginine methyl ester; 100 micromol/L), whether LPC was added or not. The ACh-induced vasorelaxation was partially inhibited by PLA(2) inhibitors methyl arachidonyl fluorophosphonate (25 micromol/L) and arachidonyl trifluoromethyl ketone (20 micromol/L) as well as by the combination of 2 Ca(2+)-dependent potassium (K(Ca)) channel inhibitors charybdotoxin (0.1 micromol/L) plus apamin (0.3 micromol/L). In the presence of LPC (20 micromol/L), ACh-induced vasorelaxation was abolished by these inhibitors. These effects were not influenced by DHA or EPA diet. Our results suggested that EPA- or DHA-supplemented diet did not exhibit any beneficial effect against LPC-induced inhibition of endothelium-dependent aortic relaxation in Golden Syrian hamsters. These LPC effects were associated in our study not only with an inhibition of nitric oxide-dependent vasorelaxation, but also with a concomitant activation of a compensatory vasorelaxant pathway depending both on PLA(2) metabolites and on K(Ca) channel opening.
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Endotélio Vascular/efeitos dos fármacos , Ácidos Graxos Ômega-3/administração & dosagem , Lisofosfatidilcolinas/administração & dosagem , Acetilcolina/farmacologia , Animais , Aorta Torácica , Cricetinae , Suplementos Nutricionais , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiologia , Inibidores Enzimáticos/farmacologia , Técnicas In Vitro , Mesocricetus , Relaxamento Muscular/efeitos dos fármacos , Relaxamento Muscular/fisiologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Nitroprussiato/farmacologia , Inibidores de Fosfolipase A2 , Fosfolipases A2/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/metabolismo , Distribuição AleatóriaRESUMO
The present study aimed to assess the effects of a COX-2 inhibitor, celecoxib, a HMG-CoA reductase inhibitor, atorvastatin, and the association of both on monocrotaline (MC)-induced pulmonary hypertension in rats. Celecoxib (Cib, 25 mg kg(-1) day(-1)), atorvastatin (AS, 10 mg kg(-1) day(-1)) or vehicle, were given orally, separately or in combination, for 26 days to Wistar male rats injected or not with MC (60 mg/kg intraperitoneally). At 4 weeks, MC-injected rats developed a severe pulmonary hypertension, with an increase in lung to body weight ratio (L/BW), right ventricular pressure (RVP in mmHg, 31 +/- 3 and 14 +/- 1 for MC and control groups, respectively, P < 0.05) and right ventricle/left ventricle + septum weight ratio (RV/LV+S) associated with a decrease in acetylcholine- and sodium-nitroprusside-induced pulmonary artery vasodilation in vitro. Hypertensive pulmonary arteries exhibited an increase in wall thickness (wall thickness to external diameter ratio, 0.42 +/- 0.01 vs 0.24 +/- 0.01 for MC and control groups, respectively, P < 0.001). Whole lung eNOS expression was decreased, and an increase in apoptosis, evaluated by cleaved caspase-3 expression, was evidenced by Western blotting. Cib (RVP in mmHg, 19 +/- 3 and 31 +/- 3 for MC+Cib and MC groups, respectively, P < 0.05), but neither AS nor AS+Cib significantly limited the development of pulmonary hypertension (P < 0.05), although the three treatments exhibited protective effects against MC-induced lung and right ventricle hypertrophy evaluated by L/BW and RV/(LV+S) ratios, respectively (P < 0.05). AS, Cib and AS+Cib treatments reduced MC-induced thickening of small intrapulmonary artery wall (0.42 +/- 0.01, 0.24 +/- 0.01, 0.26 +/- 0.01 and 0.28 +/- 0.01 for MC, MC+AS, MC+Cib and MC+AS+Cib groups, respectively, P < 0.001). In control rats, Cib reduced acetylcholine-induced pulmonary artery vasorelaxation. Treatment of MC rats by either Cib or AS did not modify acetylcholine-induced pulmonary artery relaxation, whereas combination of both drugs significantly worsened it (P < 0.05). AS, but neither Cib nor the combination of both, prevented apoptosis (AS, P < 0.05) and partially restored eNOS expression (AS, P < 0.05) in whole lung of MC rats. In conclusion, celecoxib exhibited beneficial effects against the development of monocrotaline-induced pulmonary artery hypertension and right ventricular hypertrophy. These beneficial effects of celecoxib might be, at least partly, explained by its effects on pulmonary artery thickening and pulmonary hypertrophy, even if it did not show any effect on pulmonary artery vasorelaxation and whole lung eNOS expression or apoptosis. The combination of celecoxib and atorvastatin was unable to prevent MC-induced pulmonary hypertension, decreased endothelium-dependent vasorelaxation and showed a trend toward an increased in RVP that deserves further studies.
Assuntos
Inibidores de Ciclo-Oxigenase/uso terapêutico , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/prevenção & controle , Monocrotalina , Pirazóis/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico , Acetilcolina/farmacologia , Animais , Atorvastatina , Western Blotting , Peso Corporal/efeitos dos fármacos , Caspase 3/metabolismo , Celecoxib , Progressão da Doença , Combinação de Medicamentos , Hemodinâmica/fisiologia , Hipertrofia Ventricular Direita/patologia , Hipertrofia Ventricular Direita/prevenção & controle , Masculino , Miocárdio/patologia , Óxido Nítrico Sintase Tipo III/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Ratos , Ratos Wistar , Análise de Sobrevida , Vasodilatadores/farmacologiaRESUMO
INTRODUCTION: 5-Fluorouracil (5-FU) is currently used as a chemotherapy in several cancers such as head-and-neck (H&N) and colorectal cancers. 5-FU dosing is traditionally based on body surface area (BSA), but this strategy is usually associated with severe toxicities. 5-FU is mainly catabolized by dihydropyrimidine dehydrogenase (DPD), and 5-FU dosage adaptation according to DPD status at the first cycle of treatment is now recommended. To further optimize 5-FU-based chemotherapy, a body of evidences justifies therapeutic drug monitoring (TDM). Areas covered: 5-FU pharmacokinetics, relationships between pharmacokinetics and efficacy or toxicity of 5-FU, proofs of interest of 5-FU TDM and its practical considerations are discussed. Expert opinion: BSA-adjusted 5-FU administration is associated with a large inter-individual variability, and according to this strategy, many patients experience under- or overexposure. Moreover, relationships between 5-FU area under the curve (AUC) and its toxicity or efficacy have been demonstrated, at least in patients with colorectal or H&N cancers. 5-FU therapeutic index has been validated and algorithms of 5-FU dosage adaptation according to its AUC are now available. Advances in pre-analytical and analytical steps of 5-FU TDM make its use feasible in clinical practice. Thus, there are consistent evidences to recommend 5-FU TDM in patients with advanced colorectal or H&N cancers.
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Antimetabólitos Antineoplásicos/administração & dosagem , Fluoruracila/administração & dosagem , Neoplasias/tratamento farmacológico , Algoritmos , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Área Sob a Curva , Superfície Corporal , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Fluoruracila/efeitos adversos , Fluoruracila/farmacocinética , Humanos , Neoplasias/patologiaRESUMO
AIMS: 5-FU is used as the main backbone of chemotherapy regimens for patients with colorectal and other gastrointestinal cancers. Despite development of new strategies that allowed enhancing clinical effectiveness and tolerability of 5-FU, 10-30% of patients treated with 5-FU-based regimens experience severe treatment-related toxicity. In our study, we evaluated the 5-FU exposure-toxicity relationship and investigated the efficacy of PK-guided dosing in increasing tolerability of 5-FU-based chemotherapy. RESULTS: 50.7% of patients required dose adjustments after cycle 1. Percentage of patients within 5-FU AUC range was 49.3%, 66.9%, 61.0% at cycle 1, 2 and 3 respectively (p = 0.002 cycle 1 vs cycle 2). At all 3 cycles, lower incidences of grade I/II toxicities were observed for patients below or within range compared with those above range (19.4% vs 41.3%, p < 0.001 respectively). CONCLUSIONS: Our analysis confirms that the use of BSA-guided dosing results in highly variable 5-FU exposure and strongly suggests that PK-guided dosing can improve tolerability of 5-FU based chemotherapy in patients with gastrointestinal cancers, thus supporting 5-FU therapeutic drug monitoring. METHODS: 155 patients with gastrointestinal cancers, who were to receive 5-FU-based regimens were included in our study. At cycle 1, the 5-FU dose was calculated using patient's Body Surface Area (BSA) method. A blood sample was drawn on Day 2 to measure 5-FU concentration. At cycle 2, the 5-FU dose was adjusted using a PK-guided dosing strategy targeting a plasma AUC range of 18-28 mg·h/L, based on cycle 1 concentration. Assessments of toxicity was performed at the beginning of every cycle.