HSPB5 Inhibition by NCI-41356 Reduces Experimental Lung Fibrosis by Blocking TGF-ß1 Signaling.

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.

Extracellular Heat Shock Proteins as Therapeutic Targets and Biomarkers in Fibrosing Interstitial Lung Diseases.

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.

[18F]FMISO PET/CT imaging of hypoxia as a non-invasive biomarker of disease progression and therapy efficacy in a preclinical model of pulmonary fibrosis: comparison with the [18F]FDG PET/CT approach.

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.

Lack of everolimus diffusion in pleural fluid during pleural progression of breast cancer: A case report.

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.

Association of 5-FU Therapeutic Drug Monitoring to DPD Phenotype Assessment May Reduce 5-FU Under-Exposure.

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.

Pathogenesis of fibrosis in interstitial lung disease.

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.

TRIM33 prevents pulmonary fibrosis by impairing TGF-ß1 signalling.

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.

How can we best monitor 5-FU administration to maximize benefit to risk ratio?

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.

[5-fluorouracil therapeutic drug monitoring: Update and recommendations of the STP-PT group of the SFPT and the GPCO-Unicancer]. / Suivi thérapeutique pharmacologique du 5-fluorouracile : mise au point et recommandations du groupe STP-PT de la SFPT et du GPCO-Unicancer.

Despite being 60-years old now, 5-FU remains the backbone of numerous regimen to treat a variety of solid tumors such as breast, head-and-neck and digestive cancers either in neo-adjuvant, adjuvant or metastatic settings. Standard 5-FU usually claims 15-40% of severe toxicities and up to 1% of toxic-death. Numerous studies show a stiff relationship between 5-FU exposure and toxicity or efficacy. In addition, 5-FU pharmacokinetics is highly variable between patients. Indeed, 80% of the 5-FU dose is catabolized in the liver by dihydropyrimidine dehydrogenase (DPD) into inactive compounds. It is now well established that DPD deficiency could lead to severe toxicities and, thus, require dose reduction in deficient patients. However, despite dosage adaptation based on DPD status, some patients may still experience under- or over-exposure, leading to inefficacy or major toxicity. The "Suivi thérapeutique pharmacologique et personnalisation des traitements" (STP-PT) group of the "Société française de pharmacologie et de thérapeutique" (SFPT) and the "Groupe de pharmacologie clinique oncologique" (GPCO)-Unicancer, based on the latest and most up-to-date literature data, recommend the implementation of 5-FU Therapeutic Drug Monitoring in order to ensure an adequate 5-FU exposure.

5-FU therapeutic drug monitoring as a valuable option to reduce toxicity in patients with gastrointestinal cancer.

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.

Pleural inhibition of the caspase-1/IL-1ß pathway diminishes profibrotic lung toxicity of bleomycin.

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.

Pharmacokinetics, pharmacodynamics and clinical efficacy of omalizumab for the treatment of asthma.

INTRODUCTION: Omalizumab is a subcutaneously administrated monoclonal anti-IgE antibody indicated in adults, adolescents and children 6 years of age and older with moderate to severe allergic asthma uncontrolled by conventional pharmacological treatments and sensitization to at least one perennial allergen. Area covered: This drug evaluation summarizes published data on pharmacokinetic and pharmacodynamic properties of omalizumab, on clinical efficacy and safety, including real-world evidence, and provides a medico-economic evaluation of the drug. Expert opinion: Omalizumab represents an efficient therapeutic option for the management of patients with uncontrolled moderate/severe allergic asthma. It provides a significant reduction in the asthma exacerbation rate with a steroid-sparing effect, an improvement in quality of life in adults and adolescents, despite a lack of evidence about its efficacy specifically in severe allergic asthma. Clinical trials have demonstrated its efficacy in the pediatric population but further real-life evidence is expected to better characterize long-term effects in this population. There is still some debate about the optimal treatment duration but, to date, it is recommended not to stop the treatment as cessation has resulted in symptom recurrence. Omalizumab is an expensive treatment, but a key therapeutic option when used for uncontrolled severe allergic asthma.

Deglycosylated bleomycin has the antitumor activity of bleomycin without pulmonary toxicity.

Bleomycin (BLM) is a potent anticancer drug used to treat different malignancies, mainly lymphomas, germ cell tumors, and melanomas. Unfortunately, BLM has major, dose-dependent, pulmonary toxicity that affects 20% of treated individuals. The most severe form of BLM-induced pulmonary toxicity is lung fibrosis. Deglyco-BLM is a molecule derived from BLM in which the sugar residue d-mannosyl-l-glucose disaccharide has been deleted. The objective of this study was to assess the anticancer activity and lung toxicity of deglyco-BLM. We compared the antitumor activity and pulmonary toxicity of intraperitoneally administrated deglyco-BLM and BLM in three rodent models. Pulmonary toxicity was examined in depth after intratracheal administration of both chemotherapeutic agents. The effect of both drugs was further studied in epithelial alveolar cells in vitro. We demonstrated in rodent cancer models, including a human Hodgkin's lymphoma xenograft and a syngeneic melanoma model, that intraperitoneal deglyco-BLM is as effective as BLM in inducing tumor regression. Whereas the antitumor effect of BLM was accompanied by a loss of body weight and the development of pulmonary toxicity, deglyco-BLM did not affect body weight and did not engender lung injury. Both molecules induced lung epithelial cell apoptosis after intratracheal administration, but deglyco-BLM lost the ability to induce caspase-1 activation and the production of ROS (reactive oxygen species), transforming growth factor-ß1, and other profibrotic and inflammatory cytokines in the lungs of mice and in vitro. Deglyco-BLM should be considered for clinical testing as a less toxic alternative to BLM in cancer therapy.

Changes in maternal blood inflammatory markers as a predictor of chorioamnionitis: a prospective multicenter study.

PROBLEM: To evaluate the inflammatory pattern in maternal circulation from women with preterm premature rupture of membranes (PPROM) considering the occurrence of histologically confirmed chorioamnionitis (HCA). METHOD OF STUDY: A prospective study was conducted in 121 women with PPROM between 24 and 34 + 0 weeks of gestation. Association between white blood cells (WBC) count, plasma CRP, IL-6, MCP-1 and IP-10 levels, and HCA was assessed. RESULTS: The rate of HCA was 44.7% (54/121). During the 5 days preceding delivery, median CRP, WBC, and IL-6 levels were significantly higher in the HCA than in no-HCA group (P < 0.001). Variations in IL-6, IP-10 levels, during the 24-72 hr before delivery, were predictors of the occurrence of HCA, but the diagnostic accuracy was low [Receiver Operating Characterictic (ROC) curve, area under the curve (AUC) = 0.56]. CONCLUSION: An increase in IL-6, CRP, IP-10 maternal plasma levels was confirmed in PPROM women with HCA. Longitudinal follow-up of these markers did not add valuable information regarding HCA.

Pharmacokinetic evaluation of esomeprazole for the treatment of gastroesophageal reflux disease.

INTRODUCTION: Proton pump inhibitors (PPIs) are widely used for the treatment of acid-related diseases such as gastroesophageal reflux disease (GERD). They are recommended by the American College of Gastroenterology for healing erosive esophagitis (EO) and as long-term treatment in patients with healed EO. The available PPIs differ somewhat in their pharmacokinetics and clinical properties, but whether these differences are of clinical relevance is a matter of debate. Some safety concerns have been raised with the use of PPIs, mostly an increased incidence of infectious diseases such as community-acquired pneumonia or Clostridium difficile diarrhea. AREAS COVERED: This article explores the results of clinical studies on the pharmacokinetics and pharmacodynamics of esomeprazole , as well as on its clinical efficacy to manage patients with GERD. EXPERT OPINION: GERD is a public health concern as its worldwide incidence and associated complications are increasing alongside the exponentially increasing problem of obesity. PPIs are the first pharmacological option because of their efficacy and overall positive risk-to-benefit ratio. Improved efficacy with the use of stereospecific isomers of PPIs, such as esomeprazole, has not yet been convincingly demonstrated. Nevertheless, because of individual experience with former treatment, some patients may report better symptom control when treated with a specific PPI rather than with others.

Interaction of thiopental with esomeprazole in critically ill patients.

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.

Effects of leptin on lipopolysaccharide-induced remodeling in an in vitro model of human myometrial inflammation.

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.

Pharmacokinetic and clinical evaluation of esomeprazole and ASA for the prevention of gastroduodenal ulcers in cardiovascular patients.

INTRODUCTION: Low-dose aspirin (ASA, 75 - 325 mg/day) is widely used for the primary and secondary prevention of cardiovascular (CV) diseases. However, the value of primary prevention ASA is uncertain as the reduction in occlusive events needs to be weighed against the significant increase in major bleedings. Prevention with antisecretory drugs has been proposed to reduce the incidence of ASA-induced gastrointestinal (GI) bleedings, but non-adherence to gastro-protection is of concern, as it significantly increases the risk of upper GI adverse events. Beside patients and physicians education, one approach to overcome non-adherence is the development of fixed-dose combination. AREA COVERED: This review explores the results of clinical studies on the influence of the combination esomeprazole (ESA) and ASA on pharmacokinetic (PK) parameters, and the role for such combination in prevention of CV events in patients at risk of gastric ulcers. EXPERT OPINION: Patients at risk of ASA-induced gastroduodenal ulcer might benefit from a fixed ASA and proton pump inhibitor (PPI) combination. PK and PD parameters suggest there is no significant interaction between these drugs. Nevertheless, attention must be paid on the appropriate use of such combination, that is, still balancing the risk:benefit ratio in a real-life setting, and any increase in the proportion of patients receiving ASA and PPI should be considered as a warning signal.

Postnatal overfeeding in rats leads to moderate overweight and to cardiometabolic and oxidative alterations in adulthood.

In contrast to the masses of data on obesity, few data are available concerning the cardiometabolic and oxidative consequences of moderate overweight. The model of postnatal overfeeding (OF) induces an increase in body weight at weaning that remains during adult life. Litters of Wistar rats were either maintained at 12 pups (normal-fed group, NF), or reduced to 3 pups at birth in order to induce OF. At 6 months of age, metabolic parameters, circulating oxidative stress and aortic and coronary vasoreactivity were assessed. Cardiac susceptibility to ischemia-reperfusion injury was also evaluated ex vivo as were markers of cardiac remodeling. OF led to an increase in body weight at weaning (+50%); the increase in body weight persisted throughout adult life, but was less marked (+10%). Significant increases in plasma levels of fasting glucose, insulin and leptin were found in OF rats. An increase in both plasma hydroperoxides and cardiac superoxide dismutase activity and a decrease in plasma ascorbate were found in OF rats. Vasoreactivity was not modified, but ex vivo, after 30 min of ischemia, isolated hearts from OF rats showed lower recovery of coronary flow along with a greater release of LDH. Studies on heart tissues showed an increase in collagen content and increased expression and activity of MMP-2. Our findings show that moderate overweight in adult rats, induced by postnatal overfeeding, leads to both metabolic and oxidative disturbances as well as a higher susceptibility to cardiac injury after ischemia ex vivo, which may be explained, at least in part, by ventricular remodeling.

[Level of evidence for therapeutic drug monitoring of everolimus]. / Évaluation du niveau de preuve du suivi thérapeutique pharmacologique de l'évérolimus.

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".