Indoxyl-sulfate activation of the AhR- NF-κB pathway promotes interleukin-6 secretion and the subsequent osteogenic differentiation of human valvular interstitial cells from the aortic valve.

BACKGROUND: Calcific aortic stenosis (CAS) is more prevalent, occurs earlier, progresses faster and has worse outcomes in patients with chronic kidney disease (CKD). The uremic toxin indoxyl sulfate (IS) is powerful predictor of cardiovascular mortality in these patients and a strong promoter of ectopic calcification whose role in CAS remains poorly studied. The objective of this study was to evaluate whether IS influences the mineralization of primary human valvular interstitial cells (hVICs) from the aortic valve. METHODS: Primary hVICs were exposed to increasing concentrations of IS in osteogenic medium (OM). The hVICs' osteogenic transition was monitored by qRT-PCRs for BMP2 and RUNX2 mRNA. Cell mineralization was assayed using the o-cresolphthalein complexone method. Inflammation was assessed by monitoring NF-κB activation using Western blots as well as IL-1ß, IL-6 and TNF-α secretion by ELISAs. Small interfering RNA (siRNA) approaches enabled us to determine which signaling pathways were involved. RESULTS: Indoxyl-sulfate increased OM-induced hVICs osteogenic transition and calcification in a concentration-dependent manner. This effect was blocked by silencing the receptor for IS (the aryl hydrocarbon receptor, AhR). Exposure to IS promoted p65 phosphorylation, the blockade of which inhibited IS-induced mineralization. Exposure to IS promoted IL-6 secretion by hVICs, a phenomenon blocked by silencing AhR or p65. Incubation with an anti-IL-6 antibody neutralized IS's pro-calcific effects. CONCLUSION: IS promotes hVIC mineralization through AhR-dependent activation of the NF-κB pathway and the subsequent release of IL-6. Further research should seek to determine whether targeting inflammatory pathways can reduce the onset and progression of CKD-related CAS.

Subtotal Nephrectomy Associated with a High-Phosphate Diet in Rats Mimics the Development of Calcified Aortic Valve Disease Associated with Chronic Renal Failure.

Introduction. This study addressed the hypothesis that subtotal nephrectomy associated with a high-phosphorus diet (5/6Nx + P) in rats represents a suitable animal model to mimic the cardiovascular consequences of chronic kidney disease (CKD) including calcified aortic valve disease (CAVD). Indeed, the latter contributes to the high morbidity and mortality of CKD patients and sorely lacks preclinical models for pathophysiological and pharmacological studies. Methods. Renal and cardiovascular function and structure were compared between sham-operated and 5/6 Nx rats + P 10 to 12 weeks after surgery. Results. As expected, 11 weeks after surgery, 5/6Nx + P rats developed CKD as demonstrated by their increase in plasma creatinine and urea nitrogen and decrease in glomerular filtration rate, estimated by using fluorescein-isothiocyanate-labelled sinistrin, anemia, polyuria, and polydipsia compared to sham-operated animals on a normal-phosphorus diet. At the vascular level, 5/6Nx + P rats had an increase in the calcium content of the aorta; a decrease in mesenteric artery dilatation in response to a stepwise increase in flow, illustrating the vascular dysfunction; and an increase in blood pressure. Moreover, immunohistology showed a marked deposition of hydroxyapatite crystals in the aortic valve of 5/6Nx + P rats. Echocardiography demonstrated that this was associated with a decrease in aortic valve cusp separation and an increase in aortic valve mean pressure gradient and in peak aortic valve velocity. Left-ventricular diastolic and systolic dysfunction as well as fibrosis were also present in 5/6Nx + P rats. Conclusion. This study demonstrates that 5/6Nx + P recapitulates the cardiovascular consequences observed in humans with CKD. In particular, the initiation of CAVD was shown, highlighting the interest of this animal model to study the mechanisms involved in the development of aortic stenosis and test new therapeutic strategies at an early stage of the disease.

Fetal and Neonatal Adverse Drug Reactions Associated with Biologics Taken During Pregnancy by Women with Autoimmune Diseases: Insights from an Analysis of the World Health Organization Pharmacovigilance Database (VigiBase®).

INTRODUCTION: Published data on the safety of biologics other than tumor necrosis factor (TNF) inhibitors during pregnancy are limited. OBJECTIVE: The aim was to detect pharmacovigilance signals for fetal and neonatal adverse drug reactions (ADRs) to biologics taken by pregnant women with autoimmune diseases. METHODS: We performed a disproportionality analysis of the World Health Organization's VigiBase® pharmacovigilance database from 1968 to June 1, 2021. Data were collected in June 2021. By using terms for different hierarchical levels of the Medical Dictionary for Regulatory Activities, we selected the following fetal or neonatal ADRs: stillbirth, premature birth, low birth weight, small for gestational age, and congenital malformations. The frequency of all identified ADRs for biologics of interest (adalimumab, infliximab, golimumab, certolizumab, etanercept, anakinra, canakinumab, tocilizumab, sarilumab, ustekinumab, guselkumab, secukinumab, ixekizumab, belimumab, abatacept, and rituximab) was compared with that of all other reports for all other drugs and quoted as the reporting odds ratio (ROR) [95% confidence interval]. Reports with known concomitant use of teratogenic drugs were excluded from the main analysis. Other analyses included ROR stratifications by therapeutic indication in the periods 1968-2021 and 2001-2021, and an analysis after excluding reports with steroids. RESULTS: In the main analysis, the RORs were particularly high for musculoskeletal malformations with anakinra (7.18 [3.50-14.73]), canakinumab (19.54 [12.82-29.79]), and abatacept (5.09 [2.77-9.33]), and for immune system disorders with canakinumab (347.88 [217.9-555.50]) and rituximab (9.27 [2.95-29.15]). After the exclusion of reports with steroids, the ROR was significant for neonatal infections with belimumab (28.49 [5.75-141.25]). CONCLUSION: We identified possible associations with some adverse fetal and neonatal outcomes, suggesting that vigilance is required when prescribing certain biologics during pregnancy.

COVID-19 in DMARD-treated patients with inflammatory rheumatic diseases: Insights from an analysis of the World Health Organization pharmacovigilance database.

BACKGROUND: To determine whether the use of disease-modifying antirheumatic drugs (DMARDs) is linked to the risk of COVID-19 among patients with inflammatory rheumatic diseases (IRDs). METHODS: We performed a disproportionality analysis of the World Health Organization pharmacovigilance database between January 1, 2020, and June 10, 2020. The frequency of COVID-19 reports for all DMARD classes identified was compared with that for all other reports for all other drugs and quoted as the reporting odds ratio (ROR) (95% confidence interval [CI]). RESULTS: Among 980,446 individual case-safety reports voluntarily recorded in the database, 398 identified COVID-19 in DMARD-treated patients with IRDs. There were 177 (44.5%) patients with rheumatoid arthritis (RA), 120 (30.1%) with ankylosing spondylitis (AS), 93 (23.4%) with psoriatic arthritis (PsA), and 8 (2.0%) with juvenile idiopathic arthritis. Most of the cases of COVID-19 occurred in patients taking anti-TNF agents (84.2%), resulting in a significant disproportionality signal (ROR [95% CI]: 8.31 [7.48-9.23]) - particularly in patients with RA, AS or PsA. A significant inverse disproportionality was found for the anti-IL-6 agent tocilizumab (ROR [95% CI]: 0.12 [0.02-0.88]) and JAK inhibitors (ROR [95% CI]: 0.33 [0.19-0.58]) in patients with RA - suggesting that these two drug classes are safer in the context of RA. CONCLUSION: Our results are in line with the literature on a potentially better safety profile for anti-IL-6 agents and JAK inhibitors. The WHO pharmacovigilance data suggest that COVID-19 is significantly more frequent in patients with IRDs treated with TNF inhibitors.

Potentially Inappropriate Prescribing for Prostatic Hyperplasia in Older Persons.

OBJECTIVES: In the context of improved medication management of older patients, we wished to evaluate the overprescription of potentially inappropriate drugs [α1-blockers and 5α-reductase inhibitors (5-ARI)] for benign prostate hyperplasia (BPH). These drugs are considered by geriatricians to increase the risk of falls and pharmacodynamic interactions, but these properties have not yet been proven. DESIGN: This was a descriptive study of drug prescriptions in a geriatric academic center. SETTING AND PARTICIPANTS: We included all patients older than 75 years who received a prescription for α1-blockers or 5-ARIs for 2 weeks in our hospital. METHODS: We evaluated the prevalence of the potentially inappropriate prescription of α1-blockers and 5-ARI in older people during hospitalization using a new tool consisting of an 8-item list of explicit indicators developed using the most recent summary of product characteristics (SmPC) and latest European Association of Urology (EAU) guidelines. RESULTS: A population of 117 patients (≥75 years) was included in the study. The median age was 84.5 (±6.3) years. The average time since urological medication prescription was 1.2 ± 1.6 years. According to explicit criteria, 84 patients (71.8%) received at least 1 potentially inappropriate urologic medication, 77 (91.7%) related to α1-blockers. Patients with a potentially inappropriate prescription for α1-blockers and/or 5-ARIs more frequently had urological assessments (P = .026), more frequently showed pharmacological interactions, with the risk of orthostatic hypotension (P = .005) or arrhythmia (P = .028), and experienced more falls in their history (P = .043). The misuse group was associated with an increased risk of falls, with an odds ratio of 3.22 (P = .039, 95% confidence interval 1.08-10.2). CONCLUSIONS AND IMPLICATIONS: In our study, potentially inappropriate prescriptions for older individuals for BPH was close to 72% and mainly involved α1-blockers. Potentially inappropriate prescriptions for BPH were associated with a threefold higher frequency of falls.

Associations between dysbiosis-inducing drugs, overall survival and tumor response in patients treated with immune checkpoint inhibitors.

BACKGROUND: There are conflicting data on the effects of dysbiosis-inducing drugs, and especially antibiotics (ATBs), on clinical outcomes in patients treated with immune checkpoint inhibitors (ICIs). There is a particular lack of data for patients with melanoma. METHODS: We performed a single-center retrospective study of the associations between ATBs and other drugs known to modify the gut microbiota (proton pump inhibitors, nonsteroidal anti-inflammatory drugs, statins, opioids, anti-vitamin K, levothyroxine, vitamin D3, antiarrhythmics, metformin and phloroglucinol), overall survival (OS) and tumor response in consecutive cancer patients (particularly those with melanoma) treated with an ICI (ipilimumab, nivolumab or pembrolizumab) over a 9-year period. RESULTS: A total of 372 patients were included. The mean ± standard deviation age was 64.0 ± 12.1 years. The most frequently prescribed ICI was nivolumab (in 58.3% of patients) and the most frequent indications were lung cancer (44.6%) and melanoma (29.6%). Overall, 112 patients (30.1%) had received ATBs. ATB use was associated with (1) shorter OS in the study population as a whole [adjusted hazard ratio [95% confidence interval (CI)]: 1.38 (1.00-1.90), p = 0.048] and in patients with melanoma [adjusted hazard ratio (95% CI): 2.60 (1.06-6.39), p = 0.037], and (2) a lower response rate in the study population as a whole [8.1%, versus 31.1% in patients not treated with ATBs; adjusted odds ratio (95% CI): 6.06 (2.80-14.53), p < 0.001] and in patients with melanoma [adjusted odds ratio (95% CI): 4.41 (1.04-22.80), p = 0.045]. Sensitivity analyses that minimized the indication bias did not reveal an association between OS and the presence of an infection requiring ATBs (quantified as the severity of infection, hospitalization for an infection, or ICI discontinuation). Other dysbiosis-inducing drugs were not associated with a difference in OS. CONCLUSION: Unlike other dysbiosis-inducing drugs, ATBs were associated with poorer clinical outcomes in ICI-treated patients overall and in the subset of patients with melanoma.

Metformin prevents stroke damage in non-diabetic female mice with chronic kidney disease.

Chronic kidney disease (CKD) worsens ischemic stroke severity in both patients and animals. In mice, these poorer functional outcomes are associated with decreased brain activity of AMP-activated protein kinase (AMPK), a molecule that recently emerged as a potential therapeutic target for ischemic stroke. The antidiabetic drug metformin, a well-known activator of AMPK, has improved stroke outcomes in diabetic patients with normal renal function. We investigated whether chronic metformin pre-conditioning can rescue AMPK activity and prevent stroke damage in non-diabetic mice with CKD. Eight-week-old female C57BL/6J mice were assigned to CKD or SHAM groups. CKD was induced through right kidney cortical electrocautery, followed by left total nephrectomy. Mice were then allocated to receive metformin (200 mg/kg/day) or vehicle for 5 weeks until stroke induction by transient middle cerebral artery occlusion (tMCAO). The infarct volumes were lower in CKD mice exposed to metformin than in vehicle-treated CKD mice 24 h after tMCAO. Metformin pre-conditioning of CKD mice improved their neurological score, grip strength, and prehensile abilities. It also enhanced AMPK activation, reduced apoptosis, increased neuron survival and decreased microglia/macrophage M1 signature gene expression as well as CKD-induced activation of the canonical NF-κB pathway in the ischemic lesions of CKD mice.

Impact of the corticosteroid indication and administration route on overall survival and the tumor response after immune checkpoint inhibitor initiation.

BACKGROUND: Based on their indications, systemic corticosteroids appear to negatively affect clinical outcomes in immune checkpoint inhibitor (ICI)-treated patients. There are few data on the influence of topical and inhaled corticosteroids on the ICIs' effectiveness. METHODS: In a single-center study, we retrospectively investigated the impact of systemic corticosteroids according to their indication [an immune-related adverse event (irAE) or another indication] on overall survival (OS) and the tumor response in all consecutive patients after initiation of ipilimumab, nivolumab or pembrolizumab over a 9-year period. The impacts of topical and inhaled corticosteroids were also examined. RESULTS: Three hundred and seventy-two patients were included. The mean ± standard deviation age was 64.0 ± 12.1 years. The most frequently prescribed ICI was nivolumab (in 58.3% of the patients) and the most frequent indications were lung cancer (44.6%) and melanoma (29.6%). Systemic corticosteroid use for an irAE did not have a negative impact on OS [adjusted hazard ratio (HR) [95% confidence interval (CI)] 1.04 (0.56-1.95), p = 0.902] or the best overall tumor response [adjusted odds ratio (OR) (95% CI) 1.69 (0.52-6.56), p = 0.413], while systemic corticosteroid use for another indication was associated with shorter OS [adjusted HR (95% CI) 1.34 (1.05-2.03), p = 0.046] and a poor best overall tumor response [adjusted OR (95% CI) 2.04 (1.07-5.80), p = 0.039] with a cumulative dose cut-off of 3215 mg prednisolone equivalent (specificity 71.4%; sensitivity 65.3%) and a time cut-off of 132 days (specificity 71.4%; sensitivity 89.8%). The use of topical corticosteroids was associated with a longer OS; this was probably due to dermatological irAEs. Inhaled corticosteroid use did not influence OS. CONCLUSION: Systemic corticosteroid use for an irAE does not impact OS or the tumor response, whereas use for other indications (themselves often associated with a worse prognosis) does. Topical and inhaled steroids do not have a negative impact on OS.

Two rapid, accurate liquid chromatography tandem mass spectrometry methods for the quantification of seven uremic toxins: An application for describing their accumulation kinetic profile in a context of acute kidney injury.

Acute kidney injury (AKI) is a frequent, serious complication in critically ill patients. Even if renal replacement therapy is rapidly initiated, AKI may lead to the acute accumulation of metabolic waste products called uremic toxins (UTs). Although the accumulation and effects of UTs have been extensively described in the setting of chronic kidney disease (CKD), few data are available for AKI. A rapid, sensitive, specific method with simple sample preparation is required to facilitate routine blood monitoring of UTs in a context of acute accumulation. We have developed and validated two fast liquid chromatography tandem mass spectrometry methods for the quantification of seven UTs in human serum. The first method (in negative ionization mode) enables the quantification of five UTs (hippuric acid (HA), indoxyl sulfate (IxS), para-cresyl sulfate (pCS), para-cresyl glucuronide (pCG), 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF)). The second method (in positive ionization mode) enables the quantification of two UTs (indole-3-acetic acid (IAA), and trimethylamine N-oxide (TMAO)). Sample preparation consisted of the deproteinization of a small volume of serum (50 µL). The run-times required to assay all the UTs in negative and positive ionization modes were only 2.5 and 2 min, respectively. In order to obtain a reliable, toxin-free matrix for the preparation of calibration standards and quality controls, serum was pretreated with activated charcoal. We used these methods to determine the time course of UT accumulation in eight patients who developed an AKI after cardiac surgery. The calibration curves ranged from 0.1 to 100 µg mL-1 for all the UTs (except for IAA: 0.5 to 100 µg mL-1), and the correlation coefficients were above 0.999 for all. The methods were reproducible, repeatable, and accurate, with all coefficients of variation and biases below 15%. The highest concentrations measured in patients with AKI were lower than those reported in CKD stages 4 and 5 but higher than those observed in patients with no impairment of renal function (particularly for IxS and pCS). Our results also highlighted low accumulation of the other toxins (IAA, HA, TMAO, pCG, and CMPF). The UT concentrations did not rise earlier than that of creatinine; although the return to baseline took longer than for creatinine for some compounds. Lastly, assessment of the time course of UT accumulation as a prognostic marker for AKI (particularly for pCS and IxS) appears to be promising and should be continued in a larger number of patients.

Ischaemic colitis associated with intravitreal administration of aflibercept: A first case report.

In patients with age-related macular degeneration (AMD), the intravitreal injection of antivascular endothelial growth factor (anti-VEGF) agents reduces disease progression and choroidal neovascularization. We report on a first case of ischaemic colitis associated with intravitreal injection of the anti-VEGF agent aflibercept in an 80-year-old female patient. Conservative treatment resulted in a favourable clinical outcome. The anti-VEGF agent was discontinued, and the symptoms did not recur. Although the intravitreal injection of anti-VEGF agents has not previously been linked to the occurrence of ischaemic colitis, consideration of aflibercept's pharmacological properties and the chronological relationship between the administration of this anti-VEGF agent and the occurrence of this systemic adverse event are strongly suggestive of a causal relationship in the present case. Although systemic complications have been rarely associated with intravitreal injections of anti-VEGF agents, physicians should be aware that novel adverse events can still occur in AMD patients treated with anti-VEGF agents.

Erythropoietin Pretreatment of Transplanted Endothelial Colony-Forming Cells Enhances Recovery in a Cerebral Ischemia Model by Increasing Their Homing Ability: A SPECT/CT Study.

Endothelial colony-forming cells (ECFCs) are promising candidates for cell therapy of ischemic diseases, as less than 10% of patients with an ischemic stroke are eligible for thrombolysis. We previously reported that erythropoietin priming of ECFCs increased their in vitro and in vivo angiogenic properties in mice with hindlimb ischemia. The present study used SPECT/CT to evaluate whether priming of ECFCs with erythropoietin could enhance their homing to the ischemic site after transient middle cerebral artery occlusion (MCAO) followed by reperfusion in rats and potentiate their protective or regenerative effect on blood-brain barrier (BBB) disruption, cerebral apoptosis, and cerebral blood flow (CBF). METHODS: Rats underwent a 1-h MCAO followed by reperfusion and then 1 d after MCAO received an intravenous injection of either PBS (control, n = 10), PBS-primed ECFCs (ECFCPBS, n = 13), or erythropoietin-primed ECFCs (ECFCEPO, n = 10). ECFC homing and the effect on BBB disruption, cerebral apoptosis, and CBF were evaluated by SPECT/CT up to 14 d after MCAO. The results were expressed as median ± interquartile range for ipsilateral-to-contralateral ratio of the activity in middle cerebral artery-vascularized territories in each hemisphere. Histologic evaluation of neuronal survival and astrocytic proliferation was performed on day 14. RESULTS: Erythropoietin priming increased homing of ECFCs to the ischemic hemisphere (ECFCPBS, 111.0% ± 16.0%; ECFCEPO, 146.5% ± 13.3%). BBB disruption was significantly reduced (control, 387% ± 153%; ECFCPBS, 151% ± 46% [P < 0.05]; ECFCEPO, 112% ± 9% [P < 0.001]) and correlated negatively with ECFC homing (Pearson r = -0.6930, P = 0.0002). Cerebral apoptosis was significantly reduced (control, 161% ± 10%; ECFCPBS, 141% ± 9% [P < 0.05]; ECFCEPO,118% ± 5% [P < 0.001]) and correlated negatively with ECFC homing (r = -0.7251, P < 0.0001). CBF was significantly restored with ECFCs and almost totally so with erythropoietin priming (control, 72% ± 2%; ECFCPBS, 90% ± 4% [P < 0.01]; ECFCEPO, 99% ± 4% [P < 0.001]) and correlated positively with ECFC homing (r = 0.7348, P < 0.0001). Immunoblocking against the CD146 receptor on ECFCs highlighted its notable role in ECFC homing with erythropoietin priming (ECFCEPO, 147% ± 14%, n = 4; ECFCEPO with antibody against CD146, 101% ± 12%, n = 4 [P < 0.05]). CONCLUSION: Priming with erythropoietin before cell transplantation is an efficient strategy to amplify the migratory and engraftment capacities of ECFCs and their beneficial impact on BBB disruption, apoptosis, and CBF.

Stability of a highly concentrated solution of epirubicin for conventional transcatheter arterial chemoembolization.

INTRODUCTION: Epirubicin is widely used for conventional transcatheter arterial chemoembolization (cTACE) in patients with hepatocellular-carcinoma. However, there is no data about its stability in solution at concentration higher than 2 mg/L, yet needed when mixing it with a standard volume of Lipiodol(®) to produce an efficient water-in-oil emulsion. The aim of this study was therefore to evaluate the stability of a highly concentrated solution of epirubicin for cTACE and verify whether epirubicin solution could be prepared in advance. MATERIALS AND METHODS: Fifty milligrams of epirubicin were dissolved in 6 mL of 0.9% sodium chloride and conditioned in brown polypropylene syringe. Physical and chemical stability assays including particles and HPLC-DAD analysis were performed in triplicate, using series of 5 syringes stored over 72 h at 4±2 °C followed by 4h at 22±4°C. RESULTS: Neither weight loss nor pH or spectrum change occurred. No haze or turbidity was observed and the number of subvisible particles was below the recommended limits. Epirubicin concentration remained above 95% of the initial value over the 72 h of storage at +4 °C followed by 4h at 22±4 °C and no degradation was observed. CONCLUSION: Epirubicin at 50mg/6 mL in 0.9% NaCl conditioned in brown propylene syringe is stable for at least 72 h at 4±2 °C with additional 4h at 22±4 °C allowing its preparation in advance for programmed cTACE and the standardization of its use in clinical practice.

Aseptic simulation test for cytotoxic drug production in isolators.

PURPOSE: The results of a media-fill test (MFT) study to validate processes for cytotoxic drug preparation inside and outside aseptic compounding isolators are presented. METHODS: Using an MFT protocol adapted to institution-specific production conditions, the pharmacy team at a hospital in France performed a series of tests to verify the efficacy of decontamination and sterile compounding procedures, as required by French compendial standards, while assessing the performance of its team of 12 isolator operators; all operators were tested on three occasions, producing 10 MFT samples per test for a total of 30 samples per operator. The team also tested alternative compounding systems (i.e., two closed-system transfer devices and a classic spike system) for use during power outages or other emergencies precluding drug preparation within isolators. MFTs were performed using a standard tryptone soy broth-based test kit under worst-case conditions. RESULTS: The hospital's facilities for cytotoxic drug preparation were found to be in conformance with applicable sterility standards. Bacterial growth was not detected in any of the MFT samples produced by isolator operators during the study (total n = 360). In one instance, an MFT sample prepared using a closed-system transfer device was found to be contaminated due to improper cleaning of the medication vial, highlighting the importance of strict adherence to proper decontamination procedures. CONCLUSION: A hospital's practices for preparation of sterile products according to applicable good manufacturing guidelines, as well as emergency procedures for cytotoxic drug preparation outside isolators, were validated by the results of an MFT study.

Cisplatin dose adjustment in patients with renal impairment, which recommendations should we follow?

BACKGROUND: Nephrotoxicity is the dose-limiting side effect of cisplatin justifying the assessment of renal function for dose adjustment. OBJECTIVE: To determine whether appropriate dose adjustment is made in patients with renal impairment using the Cockcroft-Gault (CG) or the abbreviated Modification of Diet in Renal Disease (aMDRD) formulas to estimate the glomerular filtration rate (GFR). SETTING: The study was conducted in a 1,000-bed university hospital. METHOD: Two years of cisplatin prescriptions were retrospectively compared to the 4 and 3 ranges estimated glomerular filtration rate (eGFR)-stratified dosing recommendations (4RR and 3RR respectively). MAIN OUTCOME MEASURE: Cisplatin dose in mg/m(2) based on kidney function and according to the dosing recommendations. RESULTS: Among 1,364 cycles of cisplatin, 156 (11.4 %) were prescribed for 70 patients with eGFR < 60 mL/min and a median age of 67.4 years. For 57 (36 %) of these cycles, doses were not reduced. When reduced, prescribed doses were not different than recommended doses according to 4RR using CG (% of protocol, 63 ± 12 vs. 64 ± 17) while it was significantly lower using aMDRD (% of protocol, 66 ± 12 vs. 81 ± 22, p < 0.01) and significantly higher according to 3RR using both CG and aMDRD (% of protocol, 63 ± 12 vs. 50 ± 3 and 66 ± 12 vs. 50.7 ± 4.0 respectively, p < 0.01). Prescription of at least one appropriate dose according to 4RR and using aMDRD was associated with a statistically significant higher median total cumulative dose (% of protocol, 89.9 vs. 75.1 % respectively, p < 0.01) without higher decrease of eGFR over time. CONCLUSION: Cisplatin dose adjustment in patients with renal impairment must be improved. Estimating GFR with the aMDRD formula and adding an intermediary level of dose reduction for patients with eGFR from 50 to 59.9 mL/min may result in a higher cumulative dose of cisplatin without higher renal toxicity, which may significantly impact on the effectiveness of the chemotherapy. A prospective evaluation remains needed to assess the benefit/risk ratio of this dose adaptation schedule, taking into account the variability of the GFR estimates.

Therapeutic benefit of a combined strategy using erythropoietin and endothelial progenitor cells after transient focal cerebral ischemia in rats.

OBJECTIVE: Many studies have demonstrated beneficial effects of either erythropoietin (EPO) or endothelial progenitor cell (EPC) treatment in cerebral ischemia. To improve post-ischemic tissue repair, we investigated the effect of systemic administration of endothelial colony-forming cells (ECFCs), considered as relevant endothelial progenitors due to their specific vasculogenic activity, in the presence or absence of EPO, on functional recovery, apoptosis, angiogenesis, and neurogenesis in a transient focal cerebral ischemia model in the adult rat. DESIGN: Experimental study. INTERVENTION: The rats were divided into four groups 24 hours after ischemia,, namely control, ECFCs, EPO, and ECFCs+EPO, and received a single intravenous injection of ECFCs (5 × 10(6) cells) and/or intraperitoneal administration of EPO (2500 UI/kg per day for 3 days). MEASUREMENT: Infarct volume, functional recovery, apoptosis, angiogenesis, and neurogenesis were assessed at different time points after ischemia. MAIN RESULTS: The combination of EPO and ECFCs was the only treatment that completely restored neurological function. The ECFCs+EPO treatment was also the most effective to decrease apoptosis and to increase angiogenesis and neurogenesis in the ischemic hemisphere compared to controls and to groups receiving ECFCs or EPO alone. CONCLUSION: These results suggest that EPO could act in a synergistic way with ECFCs to potentiate their therapeutic benefits.

Plasmatic level of leukocyte-derived microparticles is associated with unstable plaque in asymptomatic patients with high-grade carotid stenosis.

OBJECTIVES: This study sought to analyze whether the plasmatic level of leukocyte-derived microparticles (LMP) is associated with unstable plaques in patients with high-grade carotid stenosis. BACKGROUND: Preventive carotid surgery in asymptomatic patients is currently debated given the improvement of medical therapy. Therefore, noninvasive biomarkers that can predict plaque instability are needed. The LMPs, originating from activated or apoptotic leukocytes, are the major microparticle (MP) subset in human carotid plaque extracts. METHODS: Forty-two patients with >70% carotid stenosis were enrolled. Using a new standardized high-sensitivity flow cytometry assay, LMPs were measured before thromboendarterectomy. The removed plaques were characterized as stable or unstable using histological analysis according to the American Heart Association criteria. The LMP levels were analyzed according to the plaque morphology. RESULTS: The median LMP levels were significantly higher in patients with unstable plaque (n = 28; CD11bCD66b+ MP/µl 240 [25th to 75th percentile: 147 to 394], and CD15+ MP/µl 147 [60 to 335]) compared to patients with stable plaque (16 [0 to 234] and 55 [36 to 157]; p < 0.001 and p < 0.01, respectively). The increase in LMP levels was also significant when considering only the group of asymptomatic patients with unstable plaque (n = 10; CD11bCD66b+ MP/µl 199 [153 to 410] and CD15+ MP/µl 78 [56 to 258] compared with patients with stable plaque (n = 14; 20 [0 to 251] and 55 [34 to 102]; p < 0.05 and p < 0.05, respectively). After logistic regression, the neurologic symptoms (odds ratio: 48.7, 95% confidence interval: 3.0 to 788, p < 0.01) and the level of CD11bCD66b+ MPs (odds ratio: 24.4, 95% confidence interval: 2.4 to 245, p < 0.01) independently predicted plaque instability. CONCLUSIONS: LMP constitute a promising biomarker associated with plaque vulnerability in patients with high-grade carotid stenosis. These data provide clues for identifying asymptomatic subjects that are most at risk of neurologic events.

[Interests in angiogenesis inhibitor drugs approved for the treatment of cancers]. / Intérêts thérapeutiques des médicaments antiangiogéniques disponibles en cancérologie.

New blood vessel formation (angiogenesis) is fundamental to the process of tumor. Vascular Endothelial Growth Factors (VEGF) and their receptors are considered to be ones of the most important regulators of angiogenesis and new key targets for anti-cancer treatment. Three angiogenesis inhibitors are approved in France for patients with various malignancies. The main purpose of this review is to summarize the basic mechanisms of tumor angiogenesis and the reasons why angiogenesis inhibitors arouse therapeutic interest. However, for these drugs, fundamental pharmacodynamic effects observed in laboratory studies were not always translated to efficacy in clinical development. Moreover, many side effects were reported and may discourage from using it. Their optimal use should be necessary to minimize side effects and guarantee therapeutic progress.