Publications by authors named "Xavier Delavenne"

59 Publications

Severe inflammation, acute kidney injury, and drug-drug interaction: triple penalty for prolonged elimination of apixaban in patients with COVID-19, a grand round.

Ther Drug Monit 2021 Apr 21. Epub 2021 Apr 21.

Laboratoire de Pharmacologie - Toxicologie - Gaz du Sang, CHU de Saint-Etienne, Saint Etienne, France Service de Médecine Intensive et Réanimation G, CHU de Saint-Etienne, Saint Etienne, France INSERM U1059, Dysfonctions Vasculaires et de L'Hémostase, Université de Lyon, Saint-Etienne, France Service de Médecine Vasculaire et Thérapeutique, CHU de Saint-Etienne, Saint Etienne, France Infectious Diseases Department, CHU de Saint-Etienne, Saint Etienne, France.

Abstract: Herein, we present a case of apixaban elimination prolonged by 450% in a patient with coronavirus disease 2019 due to multiple conditions, including drug-drug interaction, severe inflammation, and acute kidney injury. Therapeutic drug monitoring (TDM) was used to explain unusual routine coagulation assays. This grand round highlights the importance of dialog between the clinician and a TDM consultant for optimal patient care.
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http://dx.doi.org/10.1097/FTD.0000000000000899DOI Listing
April 2021

Pharmacobezoar After Venlafaxine and Oxazepam Overdose: How Pharmacokinetics Could Help?-A Grand Round.

Ther Drug Monit 2021 04;43(2):143-145

Laboratoire De Pharmacologie, Toxicologie, Gaz Du Sang, Plateau De Biologie, Chu De Saint Etienne-Saint Etienne, France.

Abstract: The authors present here a case of a pharmacobezoar after drug overdose, diagnosed using multiple blood samples for TDM. This grand round highlights the importance of a dialog between a clinician and a TDM consultant for the optimal care of a patient.
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http://dx.doi.org/10.1097/FTD.0000000000000860DOI Listing
April 2021

Exposure-Response Relationship of Tranexamic Acid in Cardiac Surgery.

Anesthesiology 2021 02;134(2):165-178

Background: It is unclear whether high-dose regimens of tranexamic acid in cardiac surgery (total dose, 80 to 100 mg/kg) confer a clinical advantage over low-dose regimens (total dose, approximately 20 mg/kg), particularly as tranexamic acid-associated seizure may be dose-related. The authors' aim was to characterize the exposure-response relationship of this drug.

Methods: Databases were searched for randomized controlled trials of intravenous tranexamic acid in adult patients undergoing cardiopulmonary bypass surgery. Observational studies were added for seizure assessment. Tranexamic acid concentrations were predicted in each arm of each study using a population pharmacokinetic model. The exposure-response relationship was evaluated by performing a model-based meta-analysis using nonlinear mixed-effect models.

Results: Sixty-four randomized controlled trials and 18 observational studies (49,817 patients) were included. Seventy-three different regimens of tranexamic acid were identified, with the total dose administered ranging from 5.5 mg/kg to 20 g. The maximum effect of tranexamic acid for postoperative blood loss reduction was 40% (95% credible interval, 34 to 47%), and the EC50 was 5.6 mg/l (95% credible interval, 0.7 to 11 mg/l). Exposure values with low-dose regimens approached the 80% effective concentration, whereas with high-dose regimens, they exceeded the 90% effective concentration. The predicted cumulative blood loss up to 48 h postsurgery differed by 58 ml between the two regimens, and the absolute difference in erythrocyte transfusion rate was 2%. Compared to no tranexamic acid, low-dose and high-dose regimens increased the risk of seizure by 1.2-fold and 2-fold, respectively. However, the absolute risk increase was only clinically meaningful in the context of prolonged open-chamber surgery.

Conclusions: In cardiopulmonary bypass surgery, low-dose tranexamic acid seems to be an appropriate regimen for reducing bleeding outcomes. This meta-analysis has to be interpreted with caution because the results are observational and dependent on the lack of bias of the predicted tranexamic acid exposures and the quality of the included studies.

Editor’s Perspective:
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http://dx.doi.org/10.1097/ALN.0000000000003633DOI Listing
February 2021

Accidental apixaban intoxication in a 23-month-old child: a case report.

BMC Pediatr 2020 12 5;20(1):546. Epub 2020 Dec 5.

Laboratoire de Pharmacologie-Toxicologie-Gaz du Sang, CHU Saint-Etienne, Albert Raimond avenue, Saint-Etienne, France.

Background: Direct oral anticoagulants, such as apixaban, are increasingly used in everyday practice in order to treat or prevent thromboembolic diseases. To date, there is no available data about apixaban pharmacokinetics in children, and no intoxication has previously been described.

Case Presentation: A 23-month-old boy, with no medical history, was admitted to the emergency department 2 h after accidentally ingesting 40 mg apixaban and 0.75 mg digoxin. No adverse event was observed. Digoxin trough level was within therapeutic values. Apixaban blood concentration increased up to 1712 μg/L at H + 6 (1000-2750 μg/L using 2-5 mg/kg of apixaban in adults). The terminal half-life was 8.2 h (6-15 h in adults). The rapid elimination may explain the absence of bleeding despite high concentrations.

Conclusions: Despite an important intake of apixaban and a real disturbance in routine coagulation assays, no clinical sign of bleeding was observed, perhaps due to wide therapeutic range of apixaban. It may also be explained by its rapid elimination. Considering the high Cmax and a possible enteroenteric recycling, the use of activated charcoal should be considered in such situations in order to prevent eventual bleeding.
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http://dx.doi.org/10.1186/s12887-020-02448-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718703PMC
December 2020

Is the human model RPTEC/TERT1 a relevant model for assessing renal drug efflux?

Fundam Clin Pharmacol 2020 Nov 13. Epub 2020 Nov 13.

Dysfonction Vasculaire et Hémostase, INSERM U1059, Université Jean Monnet, Saint-Etienne, France.

Active tubular secretion plays a major role in renal excretion of drugs thanks to the presence of many membrane transporters such as ABC transporters. These proteins facilitate drug transfer into the urine and could be a source of pharmacokinetic variabilities. Up to now, several human in vitro models of proximal tubule have been proposed but few of them have been characterized for predicting drugs renal efflux. The aim of this study was to determine whether the human model RPTEC/TERT1 meets all the criteria expected of a good model to assess renal drug transport. First, in vitro barrier properties were investigated. Then, the expression of several ABC transporters was assessed by immunofluorescence and relative quantification by liquid chromatography-high-resolution mass spectrometry (LC-HRMS) in comparison to the MDCK model. Finally, bidirectional transport studies were performed to evaluate the functionality of transporters and the abilities of model to discriminate several drugs. The RPTEC/TERT1 model formed a tight structure (192 Ω.cm ) that was confirmed by paracellular permeability assays. Proteomic analysis and immunofluorescence staining showed the expression of several ABC transporters. Then, only the functionality of P-gp was confirmed by the active efflux of apixaban in this study. In addition, the RPTEC/TERT1 model presents the key criteria of a renal barrier and expresses several ABC transporters. Nevertheless, the BCRP and MRP's functionality was not confirmed and further investigations are required to valid this model as in vitro model for assessing renal drug efflux.
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http://dx.doi.org/10.1111/fcp.12631DOI Listing
November 2020

Using 99mTc-(V)-DMSA to follow the vascular calcification process in vascular smooth muscle cells based on pit-1 expression.

Q J Nucl Med Mol Imaging 2020 Jun 15. Epub 2020 Jun 15.

INSERM U1059 Dysfonction Vasculaire et Hémostase, Université de Lyon, UJM-Saint-Etienne, Saint-Étienne, France.

Background: Vascular calcification is an established feature of atherosclerosis process. The sodium/phosphate transporter PiT-1 acts as a biosensor in vascular calcification of VSMCs. [99mTc]-Pentavalent dimercaptosuccinic acid (99mTc-(V)-DMSA) was mediated by PiT-1 transporter in tumoral cells and we propose its evaluation in a vascular calcification in vitro model. The aim of this study was to determine if 99mTc-(V)-DMSA can follow the vascular calcification process in vascular smooth muscle cells (VSMCs) based on PiT-1 expression.

Methods: From a rat aortic VSMC cell line (A7r5), we set up a model of calcification within 7 days using a calcifying medium containing a high inorganic phosphate concentration. Phosphocalcic deposits were monitored with Alizarin red and Von Kossa staining and with phase contrast microscopy. PiT-1 expression was evaluated with an immunofluorescence assay and osteopontin expression, with whole cell ELISA assay. 99mTc-(V)-DMSA uptake was measured in control and calcifying conditions and compared with optical microscopy evaluation.

Results: Under hyperphosphatemia conditions, the VSMC cells progressively overexpressed osteopontin protein, PiT-1 transporter, and synthetized mineralized matrix with phosphocalcic deposition. 99mTc-(V)-DMSA uptake was to 2.8+/-2.08%DA/mg-protein in control cells and 42+/-24%DA/mg-protein in calcified cells (p<0,001). PiT-1 inhibition with phosphonoformic acid completely reverse the calcium deposition as well as the 99mTc-(V)- DMSA uptake. These results demonstrated that 99mTc-(V)-DMSA in vitro uptake is mediated by PiT-1 transporter and follow the VSMC calcification process.

Conclusions: These preliminary in vitro results showed 99mTc-(V)-DMSA uptake follow the phospho-calcic deposition mediated by PiT-1 transporter. This radiotracer may have some potential to detect changes of VSMC metabolism occurring in the atherosclerosis process.
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http://dx.doi.org/10.23736/S1824-4785.20.03225-2DOI Listing
June 2020

Pharmacokinetics for haemophilia treaters: Meaning of PK parameters, interpretation pitfalls, and use in the clinic.

Thromb Res 2020 08 11;192:52-60. Epub 2020 May 11.

Unité d'Hémostase Clinique, Hôpital Cardiologique Louis Pradel, Université Lyon 1, Lyon, France.

Replacement therapy with concentrates of factor VIII or IX remains the gold standard for severe haemophilia management. The recent development of clotting factor products with extended half-life, widely available on the market since 2 years, facilitates adherence, improves considerably the patients' quality of life, and simplifies the management of breakthrough bleedings or surgery. These molecules have also brought to the limelight the concepts of optimization and personalization of anti-haemophilic prophylaxis. Pharmacokinetics (PK) is one of the tools that can help haematologists to adapt in a more objective and precise manner the prophylaxis regimen to each individual patient's specific needs. For many years, clinicians at haemophilia centres have been using some simple PK parameters, such as recovery and residual level. However, recently, they have been confronted with an important number of new PK parameters they were not familiar with, but that can be used to improve patient management. Due to the accumulation of PK data and their relative complexity, it is now necessary to analyse the relevance of the different PK parameters relative to haemophilia specificities, and also to know their limits to better use them.
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http://dx.doi.org/10.1016/j.thromres.2020.05.005DOI Listing
August 2020

Towards Optimization of Hydroxychloroquine Dosing in Intensive Care Unit COVID-19 Patients.

Clin Infect Dis 2020 11;71(16):2227-2229

Institut National de la Santé et de la Recherche Médicale U1059, Dysfonctions Vasculaires et de L'Hémostase, Université de Lyon, Saint-Etienne, France.

Hydroxychloroquine (HCQ) appears to be a promising treatment for COVID-19. However, all ongoing clinical trials with HCQ use different dosing regimens, resulting in various concentrations. Pharmacokinetic studies are therefore needed to define the optimal dosing regimen.
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http://dx.doi.org/10.1093/cid/ciaa394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184449PMC
November 2020

Direct oral anticoagulants: Still too early for prime time after pulmonary endarteriectomy?

J Thromb Haemost 2020 03;18(3):758-759

Inserm UMR1059, Sainbiose DVH, University of Saint-Etienne, Saint-Etienne, France.

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http://dx.doi.org/10.1111/jth.14706DOI Listing
March 2020

A new paradigm for personalized prophylaxis for patients with severe haemophilia A.

Haemophilia 2020 Mar 26;26(2):228-235. Epub 2020 Feb 26.

Unité d'Hémostase Clinique, Hôpital Cardiologique Louis Pradel, Université Lyon 1, Lyon, France.

Aim: For patients with severe haemophilia A, guidelines recommend prophylactic treatment with FVIII, with dose calculations targeting a predetermined FVIII trough level. However, this pharmacokinetic (PK) approach is suboptimal, with some patients experiencing breakthrough bleeds. We aimed to improve FVIII dosing by incorporating the thrombin generation assay, a global haemostasis assay whose main pharmacodynamic (PD) parameter, endogenous thrombin potential (ETP), predicts spontaneous bleeding risk.

Methods: We performed post hoc combined PK-PD modelling using data from 66 adults who received human-cl rhFVIII (Nuwiq , Octapharma AG) in a phase IIIb study. Time-to-event analyses simulated the probability of spontaneous bleeding for different FVIII exposures and baseline ETPs.

Results: Ninety-one spontaneous bleeds occurred in 20/66 patients. The relationship between FVIII:C and ETP was non-linear, and the sigmoid Emax model adequately described the data. Individual PK-PD Bayesian estimation significantly improved predictive performance. Simulations showed that the mean spontaneous annual bleeding rate decreased with increasing baseline ETP or dosing: with ETP values of 200, 400 and 600 (nmol/L)·min annual bleeding rates were 2.36, 1.25 and 0.66, respectively, on 40 IU/kg human-cl rhFVIII every 3 days; and annual bleeding rates were 2.09, 1.10, and 0.60, respectively, on 60 IU/kg every 3 days.

Conclusion: Prophylactic FVIII dosing is more clinically meaningful when incorporating ETP alongside FVIII level. For the first time, FVIII dosing can be personalized with the aim of eliminating spontaneous breakthrough bleeds.
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http://dx.doi.org/10.1111/hae.13935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154752PMC
March 2020

Efficacy and Safety of Direct Oral Anticoagulants in Kidney Transplantation: A Single-center Pilot Experience.

Transplantation 2020 12;104(12):2625-2631

Service de Néphrologie et Transplantation Adulte, Hôpital Necker-Enfants Malades, Université Paris Descartes, Assistance Publique-Hôpitaux de Paris, Paris, France.

Background: Oral anticoagulation therapy is frequently prescribed to kidney transplant recipients (KTRs) for prevention and treatment of thrombotic events. Over the past 10 y, direct oral anticoagulants (DOACs) have shown similar efficacy with a safety profile equal or superior to that of vitamin K antagonist anticoagulants (VKAs) in the general population. However, little data are available on kidney transplantation.

Methods: We investigated the efficacy (thrombotic events) and safety (hemorrhagic and other adverse events and graft outcomes) of DOACs in a cohort of KTRs with a renal function >30 mL/min. We then compared these patients to a control group treated by VKA.

Results: Fifty-two KTRs treated by DOACs between 2013 and 2018 at Necker Hospital were included. Patients were with a mean age of 62 ± 13 y old and a mean glomerular filtration rate of 59 ± 20 mL/min/1.73m. The major indication was atrial fibrillation (n = 31 [60%]). Apixaban was the most commonly used agent (n = 36 [69%]). No thrombotic complications were reported under DOAC until last follow-up (14.1 ± 13 mo). In comparison to 50 controls under VKA during the same period, the bleeding rate under DOAC was significantly lower (11.5 versus 22.9 per 100 patient-y, P = 0.037) with a hazard ratio of 0.39 (95% confidence interval, 0.19-0.85, P = 0.041). No significant changes in kidney function, rejection rate, or hemoglobin level were reported.

Conclusions: DOACs appear to be effective and safe anticoagulants in KTRs with stable renal function.
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http://dx.doi.org/10.1097/TP.0000000000003168DOI Listing
December 2020

Potential usefulness of activated charcoal (DOAC remove®) for dRVVT testing in patients receiving Direct Oral AntiCoagulants.

Thromb Res 2019 Dec 5;184:86-91. Epub 2019 Nov 5.

Service d'Hématologie Biologique, CHU Pontchaillou, Rennes, France; University of Rennes 1, CIC-Inserm1414, Rennes, France.

Introduction: Lupus Anticoagulant testing using dilute Russell Viper Venom Time (dRVVT) is challenging in patients receiving Direct Oral AntiCoagulants (DOAC) due to potential false positive results. In a multicenter study, we evaluated the in vitro removal of DOAC by activated charcoal (DOAC remove®), allowing reliable dRVVT testing.

Materials And Methods: Patient samples were analyzed before and after treatment with DOAC remove®: 49 apixaban, 48 rivaroxaban, 24 dabigatran and 30 none. DOAC plasma concentrations were measured using anti-Xa or diluted thrombin time assays. In a subset of 28 samples, DOAC concentrations were also measured using HPLC-MS/MS following treatment with DOAC remove®. DRVVT was performed using STA-Staclot dRVVT Screen®/Confirm® (Stago) or LAC-Screening®/Confirmation® (Siemens).

Results: Baseline median [min-max] concentrations were 94 [<20-479] for apixaban, 107 [<20-501] for rivaroxaban and 135 ng/mL [<20-792] for dabigatran; dRVVT screen ratio/confirm ratio was positive in 47, 90 and 42% of apixaban, rivaroxaban and dabigatran samples. Treatment with DOAC remove® did not affect dRVVT results in non-DOAC patients while it resulted in DOAC concentrations <20 ng/mL in 82, 98 and 100% of samples, respectively. Concentrations were <5 ng/mL with HPLC-MS/MS in 5 out of 10, 8 out of 10 and 7 out of 8 samples, respectively. DOAC remove® corrected DOAC interference with dRVVT assays in 76, 85 and 95% of the patients, respectively.

Conclusion: For dRVVT testing in DOAC patients, we suggest the use of DOAC remove® for every rivaroxaban sample, whereas it might only be used in positive apixaban and dabigatran samples. A residual DOAC interference cannot be ruled out in case of persisting dRVVT positive results after treatment with DOAC remove®.
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http://dx.doi.org/10.1016/j.thromres.2019.11.001DOI Listing
December 2019

In vitro assessment of P-gp and BCRP transporter-mediated drug-drug interactions of riociguat with direct oral anticoagulants.

Fundam Clin Pharmacol 2020 Feb 28;34(1):109-119. Epub 2019 Aug 28.

INSERM U1059, Laboratoire Sainbiose, Equipe Dysfonctions Vasculaires et Hémostase, Faculté de médecine de Saint-Etienne, Université de Lyon, F-42055, Saint-Etienne, France.

As an alternative to vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs) are increasingly prescribed in combination with riociguat in the treatment of chronic thromboembolic pulmonary hypertension (CTEPH). Pharmacokinetics of riociguat and DOACs are influenced by efflux transporters, such as P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). This work aimed to assess P-gp and BCRP-mediated drug-drug interactions of riociguat with DOACs using in vitro models. Bidirectional permeabilities of apixaban and rivaroxaban were investigated across MDCK-MDR1 and MDCK-BCRP models, in the absence and in the presence of increasing concentrations of riociguat (0.5-100 μm). Calculated efflux ratios were subsequently used to determine riociguat inhibition percentages and half maximal inhibitory concentration (IC50). P-gp-mediated efflux of apixaban and rivaroxaban was inhibited by 8% and 21%, respectively, in the presence of 100 μm riociguat. BCRP-mediated transport of apixaban and rivaroxaban was inhibited by 36% and 77%, respectively. IC50s of riociguat on MDCK-MDR1 and MDCK-BCRP models were higher than 100 μm for apixaban and higher than 100 μm and 46.5 μm for rivaroxaban, respectively. This work showed an in vitro inhibition of BCRP-mediated DOACs transport by riociguat. In vivo studies may be required to determine the clinical relevance of these transporter-mediated interactions.
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http://dx.doi.org/10.1111/fcp.12504DOI Listing
February 2020

Rivaroxaban pharmacodynamics in healthy volunteers evaluated with thrombin generation and the active protein C system: Modeling and assessing interindividual variability.

J Thromb Haemost 2019 10 9;17(10):1670-1682. Epub 2019 Jul 9.

Laboratoire d'Hématologie Biologique, Centre Hospitalier Universitaire Pontchaillou, Rennes, France.

Background: Rivaroxaban is a direct factor Xa inhibitor with substantial inter-individual pharmacokinetic (PK) variability. Pharmacodynamic (PD) variability, especially assessed with thrombin generation (TG), has been less documented.

Objectives: (i) To assess TG parameter time profiles in healthy volunteers, with TG being studied under different conditions and (ii) to model the relationship between rivaroxaban concentrations and TG parameters and subsequently estimate interindividual variability.

Methods: Sixty healthy male volunteers (DRIVING-NCT01627665) received a single 40-mg rivaroxaban dose. Blood sampling was performed at baseline and 10 predefined time points over 24 h. The TG was investigated with the fully automated ST-Genesia system (Stago), using two tissue-factor (TF) concentrations, in the absence (-), or presence (+) of thrombomodulin (TM) for the lowest one. The PD models were built to characterize the relationships between plasma rivaroxaban concentrations and endogenous thrombin potential (ETP) or peak height induced by the lowest TF concentration.

Results: Thrombin generation parameter time profiles with the lowest TF concentration showed a good sensitivity to rivaroxaban, especially +TM (active protein C negative feedback). The relationship between rivaroxaban concentrations and TG parameters was modeled with a sigmoidal relation. Mean rivaroxaban concentrations halving the baseline value of ETP and peak height (-TM) (C ) were of 284 and 33.2 ng/mL, respectively: +TM, C declined to 19.4 and 13.8 ng/mL, reflecting a powerful inhibitory effect. The estimated C population coefficients of variation were of 12.2% (-TM) and 31.3% (+TM) with the peak height models, 34.8% (+TM) with the ETP model.

Conclusions: This low-rivaroxaban to moderate-rivaroxaban PD variability in healthy volunteers contrasts with the substantial PK variability and deserves to be studied in different patient settings.
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http://dx.doi.org/10.1111/jth.14541DOI Listing
October 2019

Direct oral anticoagulants are associated with limited damage of endothelial cells of the blood-brain barrier mediated by the thrombin/PAR-1 pathway.

Brain Res 2019 09 20;1719:57-63. Epub 2019 May 20.

INSERM, U1059 Sainbiose, Dysfonction Vasculaire et Hémostase, Saint-Etienne, France; Université de Lyon, Saint-Etienne F-42023, France.

Anticoagulant therapy presents iatrogenic effects such as intracerebral hemorrhage (ICH). The latest anticoagulants on the market, direct oral anticoagulants (DOACs) such as apixaban, dabigatran and rivaroxaban, are reported to cause less ICH than other anticoagulants. Next to the ICH area, the thrombin is accumulated and the blood-brain barrier (BBB) is opened. The effects of thrombin on the BBB are largely mediated by the protease activated receptor (PAR) family, especially the PAR-1 isoform. Our hypothesis is that DOACs may limit the effects of thrombin on endothelial cells (of the BBB) alteration by a mechanism probably involving PAR-1 activation. To test this hypothesis in vitro, we used HBEC-5i human brain endothelial cells as a human BBB model. The effects of thrombin under warfarin, heparin, rivaroxaban, apixaban, and dabigatran treatment on endothelial cells were then investigated by measuring of permeability and junction proteins: ZO-1 and VE-cadherin expressions and PAR-1 cleavage. Depending on the anticoagulant used, we observed three profiles of response of the endothelial cells after thrombin exposure: i) dabigatran treatment allowed maintaining the tightness of the endothelial monolayer; ii) other DOACs limited thrombin-induced alteration of the endothelial monolayer; and iii) pretreatment with warfarin and heparin did not protect from thrombin-induced BBB breakdown. Pretreatment with DOACs clearly limited the impact of thrombin on PAR-1 cleavage in our model, contrary to other anticoagulants, associated with ZO-1 and VE-cadherin expressions. In conclusion, DOACs seem to limit the alteration of the monolayer of endothelial cells of the BBB mediated by the thrombin/PAR-1 pathway.
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http://dx.doi.org/10.1016/j.brainres.2019.05.024DOI Listing
September 2019

Indications and potential pitfalls of anticoagulants in pulmonary hypertension: Would DOACs become a better option than VKAs?

Blood Rev 2019 09 15;37:100579. Epub 2019 May 15.

Service de Médecine Vasculaire et Thérapeutique, CHU de Saint-Etienne, Saint-Etienne, France; INSERM, UMR1059, Equipe Dysfonction Vasculaire et Hémostase, Université Jean-Monnet, Saint-Etienne F-42055, France; INSERM, CIC-1408, CHU Saint-Etienne, Saint-Etienne F-42055, France; F-CRIN INNOVTE Network, Saint-Etienne, France. Electronic address:

Pulmonary hypertension (PH) comprises a cluster of severe conditions characterized by elevated mean pulmonary arterial pressure. While targeted therapies have been approved over the last twenty years for pulmonary arterial hypertension (PAH) and chronic-thrombo-embolic PH (CTEPH), the possible role of anticoagulant therapy as a supportive treatment PAH is still debated. In PAH, anticoagulant use remains frequent, although evidence appear to be poor (recommendation class IIb-C in international guidelines). In CTEPH treatment, anticoagulants are highly recommended, because it often involves thrombosis (recommendation class I-C in international guidelines). Historically, PH patients have been treated with vitamin K antagonists (VKA), which are the only available oral anticoagulants. In this context, risk/benefit ratio of VKA is affected by the risk of major bleeding events. This drawback could be mitigated with direct oral anticoagulants (DOACs): in addition to being less constraining for patients, DOACs have shown a lower risk of major bleeding events in their already approved indications (venous thromboembolism, atrial fibrillation). However, DOACs have never been specifically assessed in PAH and CTEPH patients. Bioaccumulation risk should be considered if DOACs are prescribed in PAH and CTEPH patients, especially the risk of drug-drug interaction mediated by P-glycoprotein and cytochrome 3A4 with targeted therapies.
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http://dx.doi.org/10.1016/j.blre.2019.05.003DOI Listing
September 2019

Pharmacological characterization of the 3D MucilAir™ nasal model.

Eur J Pharm Biopharm 2019 Jun 3;139:186-196. Epub 2019 Apr 3.

INSERM, U1059, Dysfonction Vasculaire et Hémostase, Saint-Etienne, France; Université de Lyon, Saint-Etienne F-42023, France; Laboratoire de Pharmacologie Toxicologie Gaz du sang, CHU de Saint-Etienne, Saint-Etienne, France. Electronic address:

The preclinical evaluation of nasally administered drug candidates requires screening studies based on in vitro models of the nasal mucosa. The aim of this study was to evaluate the morpho-functional characteristics of the 3D MucilAir™ nasal model with a pharmacological focus on [ATP]-binding cassette (ABC) efflux transporters. We initially performed a phenotypic characterization of the MucilAir™ model and assessed its barrier properties by immunofluorescence (IF), protein mass spectrometry and examination of histological sections. We then focused on the functional expression of the ABC transporters P-glycoprotein (P-gp), multidrug resistance associated protein (MRP)1, MRP2 and breast cancer resistance protein (BCRP) in bidirectional transport experiments. The MucilAir™ model comprises a tight, polarized, pseudo-stratified nasal epithelium composed of fully differentiated ciliated, goblet and basal cells. These ABC transporters were all expressed by the cell membranes. P-gp and BCRP were both functional and capable of actively effluxing substrates. The MucilAir™ model could consequently represent a potent tool for evaluating the interaction of nasally administered drugs with ABC transporters.
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http://dx.doi.org/10.1016/j.ejpb.2019.04.002DOI Listing
June 2019

Predicting the dose of vancomycin in ICU patients receiving different types of RRT therapy: a model-based meta-analytic approach.

Br J Clin Pharmacol 2019 06 7;85(6):1215-1226. Epub 2019 Apr 7.

Unité de Recherche Clinique, Innovation, Pharmacologie, Hôpital Nord, Saint-Etienne, France.

Aim: Previous pharmacokinetic (PK) studies have proposed various dosing regimens for vancomycin in intensive care unit (ICU) patients undergoing renal replacement therapy (RRT), but all are restricted to specific RRT modalities. To be useful in practice, a population PK model would need to predict vancomycin clearance during any RRT modality. Development of such a model is feasible using meta-analysis of published summarized estimates of vancomycin PK parameters. Our aims were: (i) to develop and validate a population PK model for vancomycin that takes into account any RRT modalities, and (ii) to predict vancomycin dosing for RRT patients in ICU.

Methods: Vancomycin pharmacokinetics were assumed to be two-compartmental, total body clearance being the sum of non-RRT clearance and RRT-induced clearance. Drug disposition and non-RRT clearance parameters were estimated by systematic review and meta-analysis of previously published parameter estimates. The relationship between RRT-induced clearance and RRT flowrate settings was assessed using a model-based meta-analysis. Prediction performances of the PK model were assessed using external data.

Results: The meta-analyses of disposition parameters, non-RRT clearance and RRT-induced clearance included 11, 6 and 38 studies (84 RRT clearance measurements) respectively. The model performed well in predicting external individual PK data. Individual vancomycin concentrations during RRT were accurately predicted using Bayesian estimation based solely on pre-RRT measurements.

Conclusions: The PK model allowed accurate prediction of the vancomycin pharmacokinetics during RRT in ICU patients. Based on the model of RRT-induced clearance, an appropriate adjustment of the vancomycin dosing regimen could be proposed for any kind of flowrate settings.
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http://dx.doi.org/10.1111/bcp.13904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533443PMC
June 2019

Effects of heparin and derivatives on podocytes: An in vitro functional and morphological evaluation.

J Cell Physiol 2019 Jan 26. Epub 2019 Jan 26.

INSERM, U1059, Dysfonction Vasculaire et Hémostase, Saint-Etienne, France.

Unfractionated heparin (UFH) and low molecular heparin derivatives (LMWH) display numerous biological properties in addition to their anticoagulant effects. However, due to the physicochemical heterogeneity of these drugs, a better understanding concerning their effects on human cells is clearly needed. Considering that heparins are mainly excreted by the kidney, we focused our attention on the effect of UFH and LMWH on human podocytes by functional and morphological/phenotypic in vitro analyses. We demonstrated that these products differentially modulate the permeability of podocyte monolayer to albumin. The functional perturbations observed were correlated to significant cellular morphological and cytoskeletal changes, as well as a decrease in the expression of proteins involved in podocyte adherence to the extracellular matrix or intercellular interactions. This point confirms that UFH and the different LMWHs exert specific effects on podocyte permeability and underlines the need of in vitro tests to evaluate new biological nonanticoagulant properties of LMWH.
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http://dx.doi.org/10.1002/jcp.28191DOI Listing
January 2019

Dose tailoring of human cell line-derived recombinant factor VIII simoctocog alfa: Using a limited sampling strategy in patients with severe haemophilia A.

Br J Clin Pharmacol 2019 04 13;85(4):771-781. Epub 2019 Feb 13.

Unité d'Hémostase Clinique, Hôpital Cardiologique Louis Pradel, Université Lyon 1, Lyon, France.

Aims: The use of factor VIII (FVIII) prophylaxis in haemophilia A is considered the standard of care, particularly in children. Despite adjustment of doses for body weight and/or age, a large pharmacokinetic (PK) variability between patients has been observed. PK-tailored prophylaxis may help clinicians adjust coagulation factor FVIII activity (FVIII:C) to the desired level, which may differ in individual patients. The objective was to develop a population PK model for simoctocog alfa based on pooled clinical trial data and to develop a Bayesian estimator to allow PK parameters in individual patients to be estimated using a reduced number of blood samples.

Methods: PK data from 86 adults and 29 children/adolescents with severe haemophilia A were analysed. The FVIII data measured using 2 different assays (chromogenic and the 1-stage clotting assay) were fit to separate develop population PK models using nonlinear mixed-effect models. A Bayesian estimator was then developed to estimate the time above the threshold of 1%.

Results: The PK data for chromogenic and the 1-stage clotting assays were both best described by a 2-compartment models. Simulations demonstrated good predictive capacity. The limited sampling strategy using blood sample at 3 and 24 hours allowed an accurate estimation of the time above the threshold of 1% FVIII:C (mean bias 0.01 and 0.11, mean precision 0.18 and 0.45 for 2 assay methods).

Conclusion: In this study, we demonstrated that a Bayesian approach can help to reduce the number of samples required to estimate the time above the threshold of 1% FVIII:C with good accuracy.
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http://dx.doi.org/10.1111/bcp.13858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422655PMC
April 2019

Assessment of HBEC-5i endothelial cell line cultivated in astrocyte conditioned medium as a human blood-brain barrier model for ABC drug transport studies.

Int J Pharm 2018 Nov 18;551(1-2):281-289. Epub 2018 Sep 18.

INSERM, U1059 Sainbiose, Dysfonction Vasculaire et Hémostase, Saint-Etienne, France; Université de Lyon, Saint-Etienne, F-42023, France.

Endothelial cells are main components of the Blood-Brain Barrier (BBB) and form a tight monolayer that regulates the passage of molecules, with the ATP-Binding Cassette (ABC) transporters efflux pumps. We have developed a human in vitro model of HBEC-5i endothelial cells cultivated alone or with human astrocytes conditioned medium on insert. HBEC-5i cells showed a tight monolayer within 14 days, expressing ZO-1 and claudin 5, a low apparent permeability to small molecules, with a TEER stability during five days. The P-gp, BCRP, MRPs transporters were well expressed and functional. Accumulation and efflux ratio measurement with different ABC transporters substrates (Rhodamine 123, BCECF AM, Hoechst 33342) and inhibitors (verapamil, Ko143, probenecid and cyclosporin A) were conducted. At barrier level, the functionality of ABC transporters was three-fold enhanced in astrocyte conditioned medium. We validated our model by the transport of pharmacological substrates: caffeine, rivaroxaban, and methotrexate. The rivaroxaban and methotrexate were released with an efflux ratio >3 and were decreased by more than half with inhibitors. HBEC-5i model could be used as relevant tool in preclinical studies for assessing the permeability of therapeutic molecules to cross human BBB.
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http://dx.doi.org/10.1016/j.ijpharm.2018.09.040DOI Listing
November 2018

Pharmacological Characterization of the RPMI 2650 Model as a Relevant Tool for Assessing the Permeability of Intranasal Drugs.

Mol Pharm 2018 06 10;15(6):2246-2256. Epub 2018 May 10.

Dysfonction Vasculaire et Hémostase , INSERM, U1059 , Saint-Etienne CS 82301 , France.

The RPMI 2650 cell line has been described as a potent model of the human nasal mucosa. Nevertheless, pharmacological data are still insufficient, and the role of drug efflux transporters has not been fully elucidated. We therefore pursued the pharmacological characterization of this model, initially investigating the expression of four well-known adenosine triphosphate [ATP]-binding cassette (ABC) transporters (P-glycoprotein (P-gp), multidrug resistance associated protein (MRP)1, MRP2, and breast cancer resistance protein (BCRP)) by means of ELISA and immunofluorescence staining. The functional activity of the selected transporters was assessed by accumulation studies based on specific substrates and inhibitors. We then performed standardized bidirectional transport experiments under air-liquid interface (ALI) culture conditions, using four therapeutic compounds of local intranasal relevance in upper airway diseases. Protein expression of P-gp, MRP1, MRP2, and BCRP was detected at the membrane of the RPMI 2650 cells. In addition, all four transporters exhibited functional activity at the cellular level. In the bidirectional transport experiments, the RPMI 2650 model was able to accurately discriminate the four therapeutic compounds according to their physicochemical properties. The ABC transporters tested did not play a major role in the efflux of these compounds at the barrier level. In conclusion, the RPMI 2650 model represents a promising tool for assessing the nasal absorption of drugs on the basis of preclinical pharmacological data.
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http://dx.doi.org/10.1021/acs.molpharmaceut.8b00087DOI Listing
June 2018

In Vitro Assessment of Pharmacokinetic Drug-Drug Interactions of Direct Oral Anticoagulants: Type 5-Phosphodiesterase Inhibitors Are Inhibitors of Rivaroxaban and Apixaban Efflux by P-Glycoprotein.

J Pharmacol Exp Ther 2018 06 23;365(3):519-525. Epub 2018 Mar 23.

INSERM UMR 1059, Equipe Dysfonctions Vasculaires et de l' Hémostase, Faculté de Médecine de St-Etienne, Université Jean Monnet, Saint-Etienne, France (V.M.-C., S.H., E.J., O.D., X.D.); and Service de Médecine Vasculaire et Thérapeutique, CHU de St-Etienne, Saint-Etienne, France (L.B.)

Because of their lower bleeding risk and simplicity of use, direct oral anticoagulants (DOACs) could represent an interesting alternative to conventional anticoagulant treatment with vitamin K antagonists for patients with pulmonary arterial hypertension (PAH). P-glycoprotein (P-gp) plays a key role in DOAC pharmacokinetics. Type 5-phosphodiesterase inhibitors (PDE5is), a drug class commonly used in the treatment of PAH, have been shown to strongly inhibit P-gp. This work aimed to assess potential P-gp-mediated drug-drug interactions between PDE5is and DOACs using in vitro methods. A cellular model of drug transport assay, using P-gp-overexpressing Madin-Darby canine kidney cells (transfected with the human P-gp gene), was used to determine the bidirectional permeabilities of two DOACs (rivaroxaban and apixaban) in the absence and presence of increasing concentrations (0.5-100 M) of three PDE5is (sildenafil, tadalafil, and vardenafil). Permeabilities and efflux ratios were calculated from DOAC concentrations, were measured with liquid chromatography coupled with mass spectrometry, and were subsequently used to determine the PDE5i percentage of inhibition and half maximal inhibitory concentration (IC ). Rivaroxaban efflux was inhibited by 99%, 66%, and 100% with 100 M sildenafil, tadalafil, and vardenafil, respectively. Similarly, apixaban efflux was inhibited by 97%, 74%, and 100%, respectively. The IC values of the three PDE5is were 8, 28, and 5 M for rivaroxaban and 23, 15, and 3 M for apixaban, respectively. This study showed strong in vitro inhibition of DOAC efflux by PDE5is. In vivo studies are required to determine the clinical relevance of these interactions.
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http://dx.doi.org/10.1124/jpet.117.245993DOI Listing
June 2018

Immunosuppression by a subconjunctival implant releasing dexamethasone in a rabbit model of penetrating keratoplasty.

Br J Ophthalmol 2018 05 3;102(5):692-699. Epub 2018 Feb 3.

Corneal Graft Biology, Engineering and Imaging Laboratory (BiiGC), EA2521, SFR143, Universite Jean Monnet, Saint-Etienne, France.

Aims: To evaluate the efficacy of a subconjunctival dexamethasone-releasing implant in preventing rejection of penetrating keratoplasty (PK) in an animal model.

Methods: Twenty-two rabbits underwent allogenic PK. After randomisation, they received either a 700 µg dexamethasone implant under the conjunctiva at the end of surgery (n=10), one dexamethasone 1 mg/mL eye-drop thrice daily (n=6) or a placebo thrice daily (n=6). The suture was left in place. Animals were observed weekly by slit-lamp and optical coherence tomography with quantification of transparency, neovascularisation and central corneal thickness (CCT). At 5-6 weeks, they were euthanised for histology. The residual dexamethasone concentration in ocular tissues was measured with an ultra-performance liquid chromatography-tandem mass spectrometer.

Results: Placebo group: early neovascularisation was systematic, penetrating the graft by 270-360° at 5-6 weeks. Rejection occurred in 50% of cases. Eye-drop and implant groups: similar course without rejection at 6 weeks and normal CCT. Neovascularisation was observed in 5/6 rabbits in the eye-drop group and in 6/8 in the implant group, with two cases of new vessels penetrating the graft from week 3. Neovascularisation scores did not differ significantly between the two treatments and were significantly lower than for the placebo. Histology was in agreement in all cases. Implants disappeared after 3-5 weeks. No local side effect was observed. Tissue concentrations were all higher at day 8 (n=2) in the implant group than in the eye drop group and lower at 6 weeks (n=8).

Conclusions: In this PK model characterised by a high rejection rate, a subconjunctival dexamethasone implant was for 6 weeks as effective as the topical form in preventing allograft rejection.
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http://dx.doi.org/10.1136/bjophthalmol-2017-310734DOI Listing
May 2018

Is tranexamic acid exposure related to blood loss in hip arthroplasty? A pharmacokinetic-pharmacodynamic study.

Br J Clin Pharmacol 2018 02 28;84(2):310-319. Epub 2017 Nov 28.

INSERM, U1059, Dysfonction Vasculaire et Hémostase, F-42023, Saint-Etienne, France.

Aims: Tranexamic acid (TXA) is an antifibrinolytic agent, decreasing blood loss in hip arthroplasty. The present study investigated the relationship between TXA exposure markers, including the time above the in vitro threshold reported for inhibition of fibrinolysis (10 mg l ), and perioperative blood loss.

Methods: Data were obtained from a prospective, double-blind, parallel-arm, randomized superiority study in hip arthroplasty. Patients received a preoperative intravenous bolus of TXA 1 g followed by a continuous infusion of either TXA 1 g or placebo over 8 h. A population pharmacokinetic study was conducted to quantify TXA exposure.

Results: In total, 827 TXA plasma concentrations were measured in 166 patients. A two-compartment model fitted the data best, total body weight determining interpatient variability in the central volume of distribution. Creatinine clearance accounted for interpatient variability in clearance. At the end of surgery, all patients had TXA concentrations above the therapeutic target of 10 mg l . The model-estimated time during which the TXA concentration was above 10 mg l ranged from 3.3 h to 16.3 h. No relationship was found between blood loss and either the time during which the TXA concentration exceeded 10 mg l or the other exposure markers tested (maximum plasma concentration, area under the concentration-time curve).

Conclusion: In hip arthroplasty, TXA plasma concentrations were maintained above 10 mg l during surgery and for a minimum of 3 h with a preoperative TXA dose of 1 g. Keeping TXA concentrations above this threshold up to 16 h conferred no advantage with regard to blood loss.
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http://dx.doi.org/10.1111/bcp.13460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777664PMC
February 2018

Glomerular filtration drug injury: In vitro evaluation of functional and morphological podocyte perturbations.

Exp Cell Res 2017 12 31;361(2):300-307. Epub 2017 Oct 31.

INSERM, U1059, Dysfonction Vasculaire et Hémostase, Saint-Etienne, France; Université de Lyon, Saint-Etienne F-42023, France; Laboratoire de Pharmacologie Toxicologie, CHU Saint-Etienne, F-42055 Saint-Etienne, France.

The kidney is an organ that plays a major role in the excretion of numerous compounds such as drugs and chemicals. However, a great number of pharmacological molecules are nephrotoxic, affecting the efficiency of the treatment and increasing morbidity or mortality. Focusing on glomerular filtration, we propose in this study a simple and reproducible in vitro human model that is able to bring to light a functional podocyte injury, correlated with morphologic/phenotypic changes after drug exposure. This model was used for the evaluation of paracellular permeability of FITC-dextran molecules as well as FITC-BSA after different treatments. Puromycin aminonucleoside and adriamycin, compounds known to induce proteinuria in vivo and that serve here as positive nephrotoxic drug controls, were able to induce an important increase in fluorescent probe passage through the cell monolayer. Different molecules were then evaluated for their potential effect on podocyte filtration. Our results demonstrated that a drug effect could be time dependent, stable or scalable and relatively specific. Immunofluorescence studies indicated that these functional perturbations were due to cytoskeletal perturbations, monolayer disassembly or could be correlated with a decrease in nephrin expression and/or ZO-1 relocation. Taken together, our results demonstrated that this in vitro human model represents an interesting tool for the screening of the renal toxicity of drugs.
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http://dx.doi.org/10.1016/j.yexcr.2017.10.031DOI Listing
December 2017

In Vitro Comparison of the Role of P-Glycoprotein and Breast Cancer Resistance Protein on Direct Oral Anticoagulants Disposition.

Eur J Drug Metab Pharmacokinet 2018 Apr;43(2):183-191

INSERM, U1059, Dysfonction Vasculaire et Hémostase, Saint-Étienne, France.

Background: Pharmacokinetics of direct oral anticoagulants (DOACs) are influenced by ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP).

Objectives: To better understand the role of transporters in DOAC disposition, we evaluated and compared the permeabilities and transport properties of these drugs.

Methods: Bidirectional permeabilities of DOACs were investigated across Caco-2 cells monolayer. Transport assays were performed using different concentrations of DOAC and specific inhibitors of ABC transporters. Cell model functionality was evaluated by transport assay of two positive control substrates.

Results: The results of transport assays suggest a concentration-dependent efflux of apixaban, dabigatran etexilate and edoxaban, whereas the efflux transport of rivaroxaban did not seem to depend on concentration. Verapamil, a strong inhibitor of P-gp, decreased DOAC efflux in the Caco-2 cell model by 12-87%, depending on the drug tested. Ko143 reduced BCRP-mediated DOAC efflux in Caco-2 cells by 46-76%.

Conclusion: This study allowed identification of three different profiles of ABC carrier-mediated transport: predominantly P-gp-dependent transport (dabigatran), preferential BCRP-dependent transport (apixaban) and approximately equivalent P-gp and BCRP-mediated transport (edoxaban and rivaroxaban).
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http://dx.doi.org/10.1007/s13318-017-0434-xDOI Listing
April 2018

Evaluation of dabigatran, rivaroxaban and apixaban target-specific assays in a multicenter French study.

Thromb Res 2017 Oct 4;158:126-133. Epub 2017 Sep 4.

Hematology Laboratory, Toulouse University Hospital, Toulouse, France.

Dabigatran etexilate, rivaroxaban and apixaban (DOACs) are widely used and measurement of their concentration is desirable in certain clinical situations. Target-specific assays are available but limited information exists on their performance especially in their ability to accurately measure low and high concentrations.

Aims: To define, in a multicenter study, the precision and accuracy of DOAC measurements in daily practice.

Methods: 15 plasma samples (kindly provided by Hyphen-Biomed) spiked with 5 blinded concentrations of dabigatran, rivaroxaban or apixaban (targeted 0-40-100-250-500ng/mL, actual concentrations measured by HPLC-MS/MS), were sent to 30 haemostasis laboratories. DOAC concentration, PT and aPTT were measured once in each sample using local reagents. Interlaboratory precision was determined by its coefficient of variation (CV) and accuracy by its bias.

Results: 464 DOAC measurements were performed in the 30 laboratories using 4 dabigatran and 5 rivaroxaban/apixaban calibrated assays on 3 analysers. Inter-laboratory CVs were below 18% for concentrations ≥100ng/mL, and higher for concentrations ~40ng/mL; biases were below 8% for all drugs and concentrations. In DOAC-free samples, concentrations were all below the lower limit of quantification except for one value (dabigatran: 35ng/mL). Depending on the concentrations, significant differences were found between reagents in rivaroxaban and apixaban concentration values. PT and aPTT ratios displayed a low sensitivity to apixaban.

Conclusion: Our results suggest that calibrated DOAC assays allow the reliable measurement of a wide range of drug concentrations, even though improvement of their performances is necessary, especially for measuring low concentrations.
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http://dx.doi.org/10.1016/j.thromres.2017.09.001DOI Listing
October 2017

Intravenous Tranexamic Acid Bolus plus Infusion Is Not More Effective than a Single Bolus in Primary Hip Arthroplasty: A Randomized Controlled Trial.

Anesthesiology 2017 09;127(3):413-422

From INSERM, U1059, Hemostasis and Vascular Dysfunction, F-42023, Saint-Etienne, France (P.J.Z., J.L., C.C., X.D.); Department of Anesthesiology and Intensive Care Medicine, University Hospital of Saint-Etienne, F-42055, Saint-Etienne, France (P.J.Z., J.L., J.-Y.B., P.L., S.M.); Clinical Research Unit Innovation and Pharmacology, University Hospital of Saint-Etienne, F-42055, Saint Etienne, France (P.J.Z., C.C.); Department of Anesthesiology and Intensive Care Medicine, Northern State Medical University, Arkhangelsk, Russian Federation (D.B.B.); Orthopedic and Trauma Center, University Hospital of Saint-Etienne, F-42055, Saint-Etienne, France (R.P.); University of Lyon, Saint-Etienne, F-42023, France (R.P., X.D.); EA 7424, Inter-university Laboratory on Motor Biology, F-42023, Saint-Etienne, France (R.P.); and Laboratory of Pharmacology and Toxicology, University Hospital of Saint-Etienne, F-42055, Saint-Etienne, France (X.D.). Coordinating and Methods Center, Clinical Research Unit Innovation and Pharmacology, CHU de Saint-Etienne, F-42055, Saint-Etienne, France Coordinating and Methods Center, Clinical Research Unit Innovation and Pharmacology, CHU de Saint-Etienne, F-42055, Saint-Etienne, France Coordinating and Methods Center, Clinical Research Unit Innovation and Pharmacology, CHU de Saint-Etienne, F-42055, Saint-Etienne, France Coordinating and Methods Center, Clinical Research Unit Innovation and Pharmacology, CHU de Saint-Etienne, F-42055, Saint-Etienne, France Coordinating and Methods Center, Clinical Research Unit Innovation and Pharmacology, CHU de Saint-Etienne, F-42055, Saint-Etienne, France Department of Anesthesiology and Intensive Care Medicine, CHU de Saint-Etienne, F-42055, Saint-Etienne, France Department of Anesthesiology and Intensive Care Medicine, CHU de Saint-Etienne, F-42055, Saint-Etienne, France Department of Anesthesiology and Intensive Care Medicine, CHU de Saint-Etienne, F-42055, Saint-Etienne, France Department of Anesthesiology and Intensive Care Medicine, CHU de Saint-Etienne, F-42055, Saint-Etienne, France Department of Anesthesiology and Intensive Care Medicine, CHU de Saint-Etienne, F-42055, Saint-Etienne, France.

Background: Preoperative administration of the antifibrinolytic agent tranexamic acid reduces bleeding in patients undergoing hip arthroplasty. Increased fibrinolytic activity is maintained throughout the first day postoperation. The objective of the study was to determine whether additional perioperative administration of tranexamic acid would further reduce blood loss.

Methods: This prospective, double-blind, parallel-arm, randomized, superiority study was conducted in 168 patients undergoing unilateral primary hip arthroplasty. Patients received a preoperative intravenous bolus of 1 g of tranexamic acid followed by a continuous infusion of either tranexamic acid 1 g (bolus-plus-infusion group) or placebo (bolus group) for 8 h. The primary outcome was calculated perioperative blood loss up to day 5. Erythrocyte transfusion was implemented according to a restrictive transfusion trigger strategy.

Results: The mean perioperative blood loss was 919 ± 338 ml in the bolus-plus-infusion group (84 patients analyzed) and 888 ± 366 ml in the bolus group (83 patients analyzed); mean difference, 30 ml (95% CI, -77 to 137; P = 0.58). Within 6 weeks postsurgery, three patients in each group (3.6%) underwent erythrocyte transfusion and two patients in the bolus group experienced distal deep-vein thrombosis. A meta-analysis combining data from this study with those of five other trials showed no incremental efficacy of additional perioperative administration of tranexamic acid.

Conclusions: A preoperative bolus of tranexamic acid, associated with a restrictive transfusion trigger strategy, resulted in low erythrocyte transfusion rates in patients undergoing hip arthroplasty. Supplementary perioperative administration of tranexamic acid did not achieve any further reduction in blood loss.
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http://dx.doi.org/10.1097/ALN.0000000000001787DOI Listing
September 2017