Publications by authors named "Zoubir Djerada"

53 Publications

Anesthetic Management for Awake Tubeless Suspension Microlaryngoscopy.

Laryngoscope 2021 Apr 21. Epub 2021 Apr 21.

Department of Otorhinolaryngology-Head and Neck Surgery, Rouen University Hospital, Rouen, France.

Objectives/hypothesis: Patients' eligibility for bilateral selective laryngeal reinnervation surgery is evaluated by suspension microlaryngoscopy (SML) examination with laryngeal electromyography (LEMG). Maintaining spontaneous ventilation, with remifentanil sedation/analgesia without endotracheal tube, to allow the patient to phonate with the surgeon during awake, LEMG is a major challenge for the anesthesiologist and the otorhinololaryngologist. The objective of this study was to evaluate the safety and efficacy of a novel anesthesia protocol to manage airway access during awake tubeless SML.

Study Design: Retrospective study.

Methods: Anesthesia records of patients undergoing awake SML with LEMG were retrospectively analyzed. Procedures were performed with remifentanil sedation/analgesia with targeted controlled infusion (TCI) in combination with local anesthesia. The main outcome was the failure rate of the anesthesia protocol during the procedure. Secondary outcomes were as follows: rate of apnea requiring ventilation, airway bleeding, regurgitation, hemodynamic data as well as vasopressor use, complications, and surgeon satisfaction with the procedure.

Results: Data were obtained for 39 patients between November 2017 and September 2019, the mean age was 52 years and 29 (74%) were female. All procedures were completed without complications (0% [0-9]). Three patients (8% [1.6-20.8]) had an intraoperative episode of hypoxemia requiring mask reventilation. There was no airway bleeding, no regurgitation, and no hypotensive episode. Three patients (8% [1.6-20.8]) had noninvasive ventilation for respiratory distress after the end of the procedure.

Conclusions: Our results show that awake tubeless SML allowing phonation during LEMG can be realized under sedation and local anesthesia. However, further data are needed concerning the intraoperative and postoperative safety of the procedure.

Level Of Evidence: 4. Laryngoscope, 2021.
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http://dx.doi.org/10.1002/lary.29565DOI Listing
April 2021

Mineralocorticoid receptor blockade with finerenone improves heart function and exercise capacity in ovariectomized mice.

ESC Heart Fail 2021 Mar 20. Epub 2021 Mar 20.

Inserm U1096 ENVI, Rouen Medical School, UNIROUEN, Normandy University, Rouen, France.

Aims: In post-menopausal women, incidence of heart failure with preserved ejection fraction is higher than in men. Hormonal replacement therapies did not demonstrate benefits. We tested whether the non-steroidal mineralocorticoid receptor antagonist finerenone limits the progression of heart failure in ovariectomized (OVX) mice with metabolic disorders.

Methods And Results: Ovariectomy was performed in 4-month-old mice, treated or not at 7 months old for 1 month with finerenone (Fine) 1 mg/kg/day. Left ventricular (LV) cardiac and coronary endothelial functions were assessed by echocardiography, catheterization, and myography. Blood pressure was measured by plethysmography. Insulin and glucose tolerance tests were performed. Exercise capacity and spontaneous activity were measured on treadmill and in combined indirect calorimetric cages equipped with voluntary running wheel. OVX mice presented LV diastolic dysfunction without modification of ejection fraction compared with controls (CTL), whereas finerenone improved LV filling pressure (LV end-diastolic pressure, mmHg: CTL 3.48 ± 0.41, OVX 6.17 ± 0.30**, OVX + Fine 3.65 ± 0.55 , **P < 0.01 vs. CTL, P < 0.05 vs. OVX) and compliance (LV end-diastolic pressure-volume relation, mmHg/RVU: CTL 1.65 ± 0.42, OVX 4.77 ± 0.37***, OVX + Fine 2.87 ± 0.26 , ***P < 0.001 vs. CTL, P < 0.01 vs. OVX). Acetylcholine-induced endothelial-dependent relaxation of coronary arteries was impaired in ovariectomized mice and improved by finerenone (relaxation, %: CTL 86 ± 8, OVX 38 ± 3**, OVX + Fine 83 ± 7 , **P < 0.01 vs. CTL, P < 0.01 vs. OVX). Finerenone improved decreased ATP production by subsarcolemmal mitochondria after ovariectomy. Weight gain, increased blood pressure, and decreased insulin and glucose tolerance in OVX mice were improved by finerenone. The exercise capacity at race was diminished in untreated OVX mice only. Spontaneous activity measurements in ovariectomized mice showed decreased horizontal movements, reduced time spent in a running wheel, and reduced VO and VCO , all parameters improved by finerenone.

Conclusions: Finerenone improved cardiovascular dysfunction and exercise capacity after ovariectomy-induced LV diastolic dysfunction with preserved ejection fraction.
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http://dx.doi.org/10.1002/ehf2.13219DOI Listing
March 2021

Neglecting Plasma Protein Binding in COVID-19 Patients Leads to a Wrong Interpretation of Lopinavir Overexposure.

Clin Pharmacol Ther 2021 04 9;109(4):1030-1033. Epub 2021 Mar 9.

INTHERES, Université de Toulouse, INRA, ENVT, Toulouse Cedex 3, France.

Boffito et al. recalled the critical importance to correctly interpret protein binding. Changes of lopinavir pharmacokinetics in coronavirus disease 2019 (COVID-19) are a perfect illustration. Indeed, several studies described that total lopinavir plasma concentrations were considerably higher in patients with severe COVID-19 than those reported in patients with HIV. These findings have led to a reduction of the dose of lopinavir in some patients, hypothesizing an inhibitory effect of inflammation on lopinavir metabolism. Unfortunately, changes in plasma protein binding were never investigated. We performed a retrospective cohort study. Data were collected from the medical records of patients hospitalized for COVID-19 treated with lopinavir/ritonavir in intensive care units or infectious disease departments of Toulouse University Hospital (France). Total and unbound concentrations of lopinavir, C reactive protein, albumin, and alpha-1-acid glycoprotein (AAG) levels were measured during routine care on the same samples. In patients with COVID-19, increased total lopinavir concentration is the result of an increased AAG-bound lopinavir concentration, whereas the unbound concentration remains constant, and insufficient to reduce the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral load. Although international guidelines have recently recommended against using lopinavir/ritonavir to treat severe COVID-19, the description of lopinavir pharmacokinetics changes in COVID-19 is a textbook case of the high risk of misinterpretation of a total drug exposure when changes in protein binding are not taken into consideration.
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http://dx.doi.org/10.1002/cpt.2196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013748PMC
April 2021

Comprehensive characterisation of Culicoides clastrieri and C. festivipennis (Diptera: Ceratopogonidae) according to morphological and morphometric characters using a multivariate approach and DNA barcode.

Sci Rep 2021 Jan 13;11(1):521. Epub 2021 Jan 13.

Usc Vecpar-ANSES LSA, EA 7510, SFR Cap Santé, Université de Reims Champagne-Ardenne, 51 rue Cognacq-Jay, 51096, Reims Cedex, France.

Biting midges are widespread around the world and play an essential role in the epidemiology of over 100 veterinary and medical diseases. For taxonomists, it is difficult to correctly identify species because of affinities among cryptic species and species complexes. In this study, species boundaries were examined for C. clastrieri and C. festivipennis and compared with six other Culicoides species. The classifiers are partial least squares discriminant analysis (PLS-DA) and sparse partial least squares discriminant analysis (sPLS-DA).The performance of the proposed method was evaluated using four models: (i) geometric morphometrics applied to wings; (ii) morphological wing characters, (iii) "Full wing" (landmarks and morphological characters) and (iv)  "Full model" (morphological characters-wing, head, abdomen, legs-and wing landmarks). Double cross-validation procedures were used to validate the predictive ability of PLS-DA and sPLS-DA models. The AUC (area under the ROC curve) and the balanced error rate showed that the sPLS-DA model performs better than the PLS-DA model. Our final sPLS-DA analysis on the full wing and full model, with nine and seven components respectively, managed to perfectly classify our specimens. The C. clastrieri and C. festivipennis sequences, containing both COI and 28S genes, revealed our markers' weak discrimination power, with an intraspecific and interspecific divergence of 0.4% and 0.1% respectively. Moreover, C. clastrieri and C. festivipennis are grouped in the same clade. The morphology and wing patterns of C. clastrieri and C. festivipennis can be used to clearly distinguish them. Our study confirms C. clastrieri and C. festivipennis as two distinct species. Our results show that caution should be applied when relying solely on DNA barcodes for species identification or discovery.
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http://dx.doi.org/10.1038/s41598-020-78053-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806617PMC
January 2021

Cardiopulmonary bypass increases endothelial dysfunction after pulmonary ischaemia-reperfusion in an animal model.

Eur J Cardiothorac Surg 2020 Dec 4. Epub 2020 Dec 4.

Normandie Univ, UNIVROUEN, INSERM U1096, Rouen, France.

Objectives: Endothelial dysfunction during ischaemia-reperfusion (IR) is a major cause of primary graft dysfunction during lung transplantation. The routine use of cardiopulmonary bypass (CPB) during lung transplantation remains controversial. However, the contribution of CPB to pulmonary endothelial dysfunction remains unclear. The objective was to investigate the impact of CPB on endothelial dysfunction in a lung IR rat model.

Methods: Rats were allocated to 4 groups: (i) Sham, (ii) IR, (iii) CPB and (iv) IR-CPB. The primary outcome was the study of pulmonary vascular reactivity by wire myograph. We also assessed glycocalyx degradation by enzyme-linked immunosorbent assay and electron microscopy and both systemic and pulmonary inflammation by enzyme-linked immunosorbent assay and immunohistochemistry. Rats were exposed to 45 min of CPB and IR. We used a CPB model allowing femoro-femoral support with left pulmonary hilum ischaemia for IR.

Results: Pulmonary endothelium-dependent relaxation to acetylcholine was markedly reduced in the IR-CPB group (10.7 ± 9.1%) compared to the IR group (50.5 ± 5.2%, P < 0.001), the CPB group (54.1 ± 4.7%, P < 0.001) and the sham group (80.8 ± 6.7%, P < 0.001), suggesting that the association of pulmonary IR and CPB increases endothelial dysfunction. In IR-CPB, IR and CPB groups, vasorelaxation was completely abolished when inhibiting nitric oxide synthase, suggesting that this relaxation process was mainly mediated by nitric oxide. We observed higher syndecan-1 plasma levels in the IR-CPB group in comparison with the other groups, reflecting an increased degradation of glycocalyx. We also observed higher systemic inflammation in the IR-CPB group as shown by the increased plasma levels of IL-1β, IL-10.

Conclusions: CPB significantly increased the IR-mediated effects on pulmonary endothelial dysfunction. Therefore, the use of CPB during lung transplantation could be deleterious, by increasing endothelial dysfunction.
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http://dx.doi.org/10.1093/ejcts/ezaa412DOI Listing
December 2020

The antidiabetic drug glibenclamide exerts direct retinal neuroprotection.

Transl Res 2021 Mar 17;229:83-99. Epub 2020 Oct 17.

Université de Paris, Faculté de Santé, Paris, France; Inserm UMRS 1138, Team 17: Physiopathology of Ocular Diseases-Therapeutic Innovations, Centre de Recherche des Cordeliers, Paris, France; Sorbonne Université, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; AP-HP, OphtalmoPôle, Hôpital Cochin, Paris, France. Electronic address:

Sulfonylureas, widely used as hypoglycemic agents in adults with type 2 diabetes, have neuroprotective effects in preclinical models of central nervous system injury, and in children with neuropsychomotor impairments linked to neonatal diabetes secondary to ATP-sensitive potassium channel mutations. In the human and rodent retina, we show that the glibenclamide-activated channel sulfonylurea receptor 1 (SUR1) is expressed in the retina and enriched in the macula; we also show that it colocalizes with the potassium channel Kir6.2, and with the cation channel transporter TRPM4. Glibenclamide (glyburide), administered at doses that did not decrease the glycemia, or injected directly into the eye, protected the structure and the function of the retina in various models of retinal injury that recapitulate the pathogenic neurodegenerative events in the diabetic retina. The downregulation of SUR1 using a siRNA suppressed the neuroprotective effects of glibenclamide on excitotoxic stress-induced cell death. The glibenclamide effects include the transcriptional regulation of antioxidant and neuroprotective genes. Ocular glibenclamide could be repurposed for diabetic retinopathy.
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http://dx.doi.org/10.1016/j.trsl.2020.10.003DOI Listing
March 2021

Contributions of Emotional Overload, Emotion Dysregulation, and Impulsivity to Eating Patterns in Obese Patients with Binge Eating Disorder and Seeking Bariatric Surgery.

Nutrients 2020 Oct 12;12(10). Epub 2020 Oct 12.

Psychiatry Department, Reims University Hospital, EPSM Marne, 51100 Reims, France.

Background: Binge eating disorder (BED) is very frequently observed in patients considered for weight loss surgery and seems to influence their outcome critically. Literature highlights a global emotional overload in individuals with BED, but little is known on the mechanisms involved. The present study aimed to focus on emotion regulation, impulsivity, depression, and anxiety in people with and without BED and fulfilling inclusion criteria for bariatric surgery. Doing so, we sought to individualize factors related to BED. Then, we examined the contribution of depression, anxiety, emotion regulation difficulties, and impulsivity to inappropriate eating behaviors observed in patients with BED.

Methods: A sample of 121 individuals (79.3% female, mean age: 40.82 ± 9.26, mean current body mass index (BMI): 44.92 kg/m ± 7.55) seeking bariatric surgery were recruited at the Champagne Ardenne Specialized Center in Obesity in Reims, France from November 2017 to October 2018. They were stratified as with or without BED according to the binge eating scale. Characteristics identified in univariate analyses as differentiating the two groups were then included in multivariable analyses.

Results: Multivariable analyses showed that limited access to emotional regulation strategies was significantly associated with BED. Furthermore, inappropriate eating behaviors were independently associated with age, depression severity, anxiety, emotional dysregulation, and impulsivity in BED group.

Conclusions: The present findings are indicative of an association between emotion deficit and BED in obese patients seeking bariatric surgery. Patients with BED could benefit from the addition of an emotion regulation intervention.
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http://dx.doi.org/10.3390/nu12103099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650699PMC
October 2020

Incremental Value of CSF Biomarkers in Clinically Diagnosed AD and Non-AD Dementia.

Front Neurol 2020 25;11:560. Epub 2020 Jun 25.

Champagne-Ardenne Resource and Research Memory Center (CMRR), Maison Blanche Hospital, Reims University Hospital, Reims, France.

Cerebrospinal fluid (CSF) biomarkers are used to diagnose Alzheimer disease (AD), especially in atypical clinical presentations. No consensus currently exists regarding cut-off values. This study aimed, firstly, to define optimal cut-off values for CSF biomarkers, and secondly, to investigate the most relevant diagnostic strategy for AD based on CSF biomarker combinations. A total of 380 patients were prospectively included: 140 with AD, 240 with various neurological diagnoses (non-AD). CSF biomarkers were measured using ELISA. Univariate and multivariate analyses were performed using random forest and logistic regression approaches. Univariate receiver operating curve curves analysis of T-Tau, P-Tau, Aβ, Aβ concentrations, and Aβ/Aβ ratio levels showed AD cut-off values of ≥355, ≥57, ≤706, ≥10,854, and ≤0.059 ng/L, respectively. Multivariate analysis using random forest and logistic regression found that the algorithm based on P-Tau, Aβ concentrations and Aβ/Aβ ratio yielded the best discrimination between AD and non-AD populations. The cross-validation technique of the final model showed a mean accuracy of 0.85 and a mean AUC of 0.89. This study confirms that the Aβ/Aβ ratio was more useful than the Aβ concentration in discriminating AD from non-AD populations in daily practice. These results indicate that the Aβ/Aβ ratio should be assessed in all cases, independently of Aβ concentrations.
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http://dx.doi.org/10.3389/fneur.2020.00560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330115PMC
June 2020

Quantification of methadone, buprenorphine, naloxone, opioids, and their derivates in whole blood by liquid chromatography-high-resolution mass spectrometry: Analysis of their involvement in fatal forensic cases.

J Chromatogr B Analyt Technol Biomed Life Sci 2020 Sep 9;1152:122226. Epub 2020 Jun 9.

Department of Pharmacology, E.A.3801, SFR CAP-santé, Reims University Hospital, 51, rue Cognacq-Jay, 51095 Reims Cedex, France. Electronic address:

Opioids represent a broad family of compounds that can be used in several indications: analgesics, antitussives, opioid substitution therapy (e.g. methadone, buprenorphine…). When these products are misused, they are often addictive. Thus, we aimed to develop an analytical method able to rapidly quantify several opiates and opioids (6-monoacetylmorphine, buprenorphine, codeine, dihydrocodeine, 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine, ethylmorphine, heroin, methadone, morphine, nalbuphine, naloxone, norbuprenorphine, norcodeine, norpropoxyphene, oxycodone and propoxyphene) in whole blood by ultra-high performance liquid chromatography combined with high resolution mass spectrometry (UHPLC-HRMS). The validated assay requires only 100 µL of the blood sample. The sample is prepared by a rapid liquid-liquid extraction using 5% zinc sulfate (W/V), methanol and acetonitrile. Calibration curves range from 0.98 to 1000 µg/L, except for buprenorphine (0.39-100 µg/L) and norbuprenorphine (0.20-100 µg/L). Inter- and intra-analytical accuracy was less than 15%. Therefore, we describe the development and full validation of an accurate, sensitive and precise assay using UHPLC-HRMS for the analysis of opioids in whole blood. After validation, this new assay is successfully applied on a routine laboratory application basis.
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http://dx.doi.org/10.1016/j.jchromb.2020.122226DOI Listing
September 2020

Simultaneous quantification of 8 nucleotides and adenosine in cells and their medium using UHPLC-HRMS.

J Chromatogr B Analyt Technol Biomed Life Sci 2020 Jul 19;1148:122156. Epub 2020 May 19.

Department of Pharmacology, E.A.3801, SFR CAP-santé, Reims University Hospital, 51, rue Cognacq-Jay, 51095 Reims Cedex, France. Electronic address:

Purinergic signalling is involved in physiological processes, particularly during ischemia-reperfusion injuries for which it has a protective effect. The purpose of this work was to develop a method for simultaneous quantification of eight nucleotides and adenosine in biological matrices by liquid chromatography coupled with high-resolution mass spectrometry. A method was developed that was sufficiently robust to quantify the targeted analytes in 20 min with good sensitivity. Analysis of extracellular media from cultured endothelial cells detected the release of nucleotides and adenosine during 2 h of hypoxia. The quantification of cylic adenosine monophosphate (cAMP) allowed to establish a dose-response curve after receptor stimulation. Therefore, our method allows us to study the involvement of nucleotides in various processes in both the intracellular and extracellular compartment.
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http://dx.doi.org/10.1016/j.jchromb.2020.122156DOI Listing
July 2020

Ticagrelor Prevents Endothelial Cell Apoptosis through the Adenosine Signalling Pathway in the Early Stages of Hypoxia.

Biomolecules 2020 05 9;10(5). Epub 2020 May 9.

Department of Pharmacology, Hémostase et Remodelage Vasculaire post-Ischémie (HERVI) E.A.3801, SFR CAP-santé, Reims University Hospital, 51, rue Cognacq-Jay, 51095 Reims CEDEX, France.

Background: Several studies have reported the beneficial effects of anti-platelet drugs in cardioprotection against ischaemia-reperfusion injuries. To date, no studies have focused on the indirect cytoprotective effects of ticagrelor via adenosine receptor on the endothelium.

Method: By evaluating cell viability and cleaved caspase 3 expression, we validated a model of endothelial cell apoptosis induced by hypoxia. In hypoxic endothelial cells treated with ticagrelor, we quantified the extracellular concentration of adenosine, and then we studied the involvement of adenosine pathways in the cytoprotective effect of ticagrelor.

Results: Our results showed that 10 µM ticagrelor induced an anti-apoptotic effect in our model associated with an increase of extracellular adenosine concentration. Similar experiments were conducted with cangrelor but did not demonstrate an anti-apoptotic effect. We also found that A2B and A3 adenosine receptors were involved in the anti-apoptotic effect of ticagrelor in endothelial cells exposed to 2 h of hypoxia stress.

Conclusion: we described an endothelial cytoprotective mechanism of ticagrelor against hypoxia stress, independent of blood elements. We highlighted a mechanism triggered mainly by the increased extracellular bioavailability of adenosine, which activates A2B and A3 receptors on the endothelium.
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http://dx.doi.org/10.3390/biom10050740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277469PMC
May 2020

Real Life Population Pharmacokinetics Modelling of Eight Factors VIII in Patients with Severe Haemophilia A: Is It Always Relevant to Switch to an Extended Half-Life?

Pharmaceutics 2020 Apr 21;12(4). Epub 2020 Apr 21.

Department of Medical Pharmacology, University Hospital of Reims, EA3801, SFR Cap-Santé, University of Reims, 51100 Reims, France.

We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting the desired level of FVIII activity (FVIII:C); and (2) to compare half-life (HL) in patients switching from a standard half-life (SHL) to an extended half-life (EHL) and evaluate the relevance of the switch. One-stage clotting assay for the measurement of FVIII activity (FVIII:C, IU/mL) was used for population PK modelling. The software, Monolix version 2019R1, was used for non-linear mixed-effects modelling. A linear two-compartment model best described FVIII:C. The estimated PK parameters (between-subject variability) were: 2640 mL (23.2%) for volume of central compartment (V1), 339 mL (46.8%) for volume of peripheral compartment (V2), 135 mL/h for Q (fixed random effect), and 204 mL/h (34.9%) for clearance (Cl). Weight, age, and categorical covariate EHL were found to influence Cl and only weight for V1. This model can be used for all of the FVIII cited in the study. Moreover, we demonstrated, in accordance with previous studies, that Elocta had longer half-life (EHL) than SHL (mean ratio: 1.48) as compared to Advate, Factane, Kogenate, Novoeight, and Refacto.
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http://dx.doi.org/10.3390/pharmaceutics12040380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238177PMC
April 2020

5/6 nephrectomy induces different renal, cardiac and vascular consequences in 129/Sv and C57BL/6JRj mice.

Sci Rep 2020 01 30;10(1):1524. Epub 2020 Jan 30.

Normandie Univ, UNIROUEN, INSERM U1096, FHU REMOD-VHF, 76000, Rouen, France.

Experimental models of cardiovascular diseases largely depend on the genetic background. Subtotal 5/6 nephrectomy (5/6 Nx) is the most frequently used model of chronic kidney disease (CKD) in rodents. However, in mice, cardiovascular consequences of 5/6 Nx are rarely reported in details and comparative results between strains are scarce. The present study detailed and compared the outcomes of 5/6 Nx in the 2 main strains of mice used in cardiovascular and kidney research, 129/Sv and C57BL/6JRj. Twelve weeks after 5/6 Nx, CKD was demonstrated by a significant increase in plasma creatinine in both 129/Sv and C57BL/6JRj male mice. Polyuria and kidney histological lesions were more pronounced in 129/Sv than in C57BL/6JRj mice. Increase in albuminuria was significant in 129/Sv but not in C57BL/6JRj mice. Both strains exhibited an increase in systolic blood pressure after 8 weeks associated with decreases in cardiac systolic and diastolic function. Heart weight increased significantly only in 129/Sv mice. Endothelium-dependent mesenteric artery relaxation to acetylcholine was altered after 5/6 Nx in C57BL/6JRj mice. Marked reduction of endothelium-dependent vasodilation to increased intraluminal flow was demonstrated in both strains after 5/6 Nx. Cardiovascular and kidney consequences of 5/6 Nx were more pronounced in 129/Sv than in C57BL/6JRj mice.
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http://dx.doi.org/10.1038/s41598-020-58393-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992698PMC
January 2020

Myocardial infarction in relation to colchicine poisoning: A precipitating cause of refractory toxic cardiogenic shock.

Therapie 2021 Jan-Feb;76(1):51-53. Epub 2020 Jan 13.

Department of medical and toxicological critical care, Lariboisière hospital, Paris-Diderot University, INSERM UMRS-1144, 75010 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.therap.2019.12.012DOI Listing
January 2020

COMPARING INTRAVITREAL AIR AND GAS FOR THE TREATMENT OF VITREOMACULAR TRACTION.

Retina 2020 Nov;40(11):2140-2147

Departments of Ophthalmology, and.

Purpose: To compare the effect of intravitreal injections of air with gas on vitreomacular traction (VMT) release and attempt to analyze predictive factors for success.

Methods: The medical records of patients with symptomatic VMT undergoing intravitreal injections (0.3 mL) of either octafluoropropane (C3F8) or air were retrospectively reviewed. The VMT release (primary end point) and the best-corrected visual acuity (secondary end point) were noted 1 month after injection. At baseline and 1 month after the injection, a macular optical coherence tomography was performed.

Results: Twenty-four eyes of 22 patients were included. Vitreomacular traction was released in 10 cases, 7 among 11 C3F8-injected eyes (63%) and 3 among 13 air-injected eyes (23%) (P = 0.045). In eyes with released VMT, ETDRS improved from 61 ± 35 (0-100) to 65 ± 37 (0-100) 1 month after the injection (P = 0.03). All patients with VMT release had a horizontal vitreomacular adhesion of less than 600 µm. Five eyes (23%) underwent vitrectomy after the injection of gas or air.

Conclusion: Posterior vitreous detachment in VMT can be observed with both air and gas injection with a low complication rate. The occurrence of VMT release observed with air seemed to be less frequent than that observed with gas.
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http://dx.doi.org/10.1097/IAE.0000000000002733DOI Listing
November 2020

Intratumoral distribution of YSNSG cyclopeptide in a mouse melanoma model using microdialysis.

Eur J Pharm Sci 2020 Feb 19;143:105201. Epub 2019 Dec 19.

MEDyC Research Unit, UMR CNRS/URCA n°7369, SFR CAP-Santé, Reims University, 51, rue Cognacq-Jay, 51100 Reims, France; Department of Pharmacy, CHU Reims, Avenue du General Koenig, and Faculty of Pharmacy, Reims University, 51, rue Cognacq-Jay, 51100 Reims, France.

The YSNSG peptide is a synthetic cyclopeptide targeting αβ integrin with antitumor activity. Previous study has determined main pharmacokinetic parameters in plasma and in tissue in healthy animals using microdialysis. First we aim to assess the impact of a 20 mg/kg dosage instead of 10 mg/kg in tumor growth inhibition. Secondly we aim to investigate the YSNSG peptide distribution in two different tumor regions in animals with melanoma. C57BL/6 mice were exposed at Days 8, 10 and 12 after melanoma cells implantation (B16F1) to different dosage of YSNSG peptide or control, respectively (n = 10 per group). Data analysis was performed at D16, 20 and 24 with a Nonlinear Mixed-Effects (NLME) approach. For pharmacokinetic study n = 8 mice (same disease condition) received YSNSG peptide by intravenous after insertion of two microdialysis probes in central peripheral region of tumor, respectively. Plasma and tissue samples were collected during 2 h. A non-compartmental analysis was performed to determine main pharmacokinetic parameters. There was a significant tumor growth inhibition in mice receiving 20 mg/kg vs Control (p < 0.02). Main plasma parameters were half-life elimination 25.8 ± 8.2 min, volume of distribution 11.9 ± 0.4 mL, clearance 19.8 ± 9.4 mL/h and area under the curve 1,173.6 µg.min/mL. Penetration rate of the YSNSG peptide from plasma to tumor tissue were 3.3 ± 2.1% and 3.4 ± 2.7% in central and peripheral, respectively. Contrary to subcutaneous distribution in healthy animals the distribution of the YSNSG peptide into tumoral tissue is low but seems non-heterogeneous between central and peripheral tumor region.
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http://dx.doi.org/10.1016/j.ejps.2019.105201DOI Listing
February 2020

Population Pharmacokinetics Modelling and Simulation of Mitotane in Patients with Adrenocortical Carcinoma: An Individualized Dose Regimen to Target All Patients at Three Months?

Pharmaceutics 2019 Oct 31;11(11). Epub 2019 Oct 31.

Department of Medical Pharmacology, EA3801, SFR Cap-Santé, Reims University Hospitals, 51100 Reims, France.

Mitotane is the most effective agent in post-operative treatment of adrenocortical carcinoma. In adults, the starting dose is 2-3 g/day and should be slightly increased to reach the therapeutic index of 14-20 mg/L. This study developed a population PK model for mitotane and to simulate recommended/high dosing regimens. We retrospectively analyzed the data files of 38 patients with 503 plasma concentrations for the pharmacokinetic analysis. Monolix version 2019R1 was used for non-linear mixed-effects modelling. Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA ≥ 14 mg/L) at one month and at three months. Mitotane concentration data were best described by a linear one-compartment model. The estimated PK parameters (between-subject variability) were: 8900 L (90.4%) for central volume of distribution (V) and 70 L·h (29.3%) for clearance (Cl). HDL, Triglyceride (Tg) and a latent covariate were found to influence Cl. The PTA at three months for 3, 6, 9, and 12 g per day was 10%, 55%, 76%, and 85%, respectively. For a loading dose of 15 g/day for one month then 5 g/day, the PTA in the first and third months was 57 and 69%, respectively. This is the first PKpop model of mitotane highlighting the effect of HDL and Tg covariates on the clearance as well as a subpopulation of ultrafast metabolizer. The simulations suggest that recommended dose regimens are not enough to target the therapeutic threshold in the third month.
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http://dx.doi.org/10.3390/pharmaceutics11110566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920765PMC
October 2019

Methylphenidate and stuttering.

Br J Clin Pharmacol 2019 11 12;85(11):2634-2637. Epub 2019 Sep 12.

Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Reims University Hospitals, Reims, France.

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http://dx.doi.org/10.1111/bcp.14097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848957PMC
November 2019

Metformin-related lactic acidosis with acute kidney injury: results of a French observational multicenter study.

Clin Toxicol (Phila) 2020 05 6;58(5):375-382. Epub 2019 Aug 6.

Department of Nephrology, CHU Reims, Reims, France.

Metformin-associated lactic acidosis (MALA) and metformin-induced lactic acidosis (MILA) remain controversial entities. Metformin toxic effect depends on accumulation to lead to lactic acidosis (LA), particularly during an episode of acute kidney injury (AKI). In MILA, no other condition contributing to LA is found. The aims of this study were to describe the characteristics and prognosis of AKI associated with LA in metformin users and to clarify the role of this drug in the different types of LA. We performed a French multicenter retrospective study in diabetic patients treated by metformin presenting with LA in a context of AKI in 2015. 126 nephrology units (NU) and 23 intensive care units (ICU) were contacted. We individualized MILA and MALA patients in order to illustrate the role of metformin. We included 173 patients (109 MILA, 64 MALA). 103 patients presented without hemodynamic instability (82 MILA and 21 MALA) whereas 70 patients were shocked including 27 MILA. The shock was associated with death with an odds ratio (OR) of 12.92 ( < .001). Digestive disorders (DD) were strongly associated with MILA ( = .0001). MALA was significantly associated with shock ( < .0001). The mortality rate was higher in MALA (26%) when compared with MILA (7%). Dialysis performed in 133 patients was significantly associated with shock, kalemia, lactate and serum creatinine levels. In multivariate analysis, metformin level was independently associated with pH or lactate level only in MILA patients. MILA is associated with DD and death is due to severe refractory acidosis leading to cardiovascular collapse attributed to metformin accumulation mainly via AKI. MALA patients are more frequently shocked and death is related to their underlying condition, metformin accumulation increasing LA.
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http://dx.doi.org/10.1080/15563650.2019.1648816DOI Listing
May 2020

[Agitation and hallucinations following a poisoning by tricyclics: Two case reports].

Therapie 2020 May - Jun;75(3):311-314. Epub 2019 Apr 30.

Pôle universitaire de psychiatrie adulte, centre hospitalier universitaire de Reims, rue du général Koenig, 51100 Reims, France; Laboratoire cognition, santé, socialisation, université de Reims Champagne-Ardenne, 51100 Reims, France. Electronic address:

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http://dx.doi.org/10.1016/j.therap.2019.03.011DOI Listing
April 2019

Interest of adjusting urine cannabinoids to creatinine level to monitor cannabis cessation therapy in heavy smokers with psychiatric disorders.

Drug Test Anal 2019 Sep 25;11(9):1453-1459. Epub 2019 Jul 25.

Laboratory of Pharmacokinetics, Toxicology and Pharmacogenomics, Rouen University Hospital, 76000, Rouen, France.

Up to 25% of hospitalized patients in a psychiatric department exhibit troubles linked to cannabis use. Weaning patients with psychiatric disorders off drugs of abuse requires specific care to improve their clinical outcome. The present study aims to develop a predictive model of urinary excretion of creatinine-normalized cannabinoids (U ) and to determine U thresholds corresponding to the widely used cut-offs of 20 ng/mL and 50 ng/mL for cannabinoids. One hundred thirty-two patients with 452 urine samples were included between 2013 and 2017. Urinary cannabinoids and U elimination curves were computed for each patient. Using a mono-exponential mixed effect model with 88 samples from 26 subjects exhibiting at least 3 decreasing U in a row, the average calculated elimination rate constant was 0.0108 ± 0.0026 h , corresponding to a mean elimination half-life of 64 ± 12 hours. The use of U is of particular interest because of a high inter- and intra-individual variability of urinary creatinine concentration (from 0.06 to 3.81 mg/mL). Moreover, U allows for the detection of diluted or concentrated urine specimens that may lead to false positive (FP) or false negative (FN) results. Receiver operator characteristic (ROC) curves were used to assess U thresholds of 32.4 and 124.7 ng/mg that provide a strong discrimination between positive and negative samples for cannabinoids cut-offs of 20 and 50 ng/mL respectively. The developed model and the defined U thresholds allowed for the accurate prediction of the time needed to reach a negative U result that could be used by clinicians to optimize clinical care.
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http://dx.doi.org/10.1002/dta.2672DOI Listing
September 2019

Intravenous single administration of amiodarone and breastfeeding.

Authors:
Zoubir Djerada

Fundam Clin Pharmacol 2019 Jun;33(3):365-366

Department of Medical Pharmacology, E.A.3801, SFR CAP-santé, Reims University Hospital, 51, rue Cognacq-Jay, 51095, Reims Cedex, France.

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http://dx.doi.org/10.1111/fcp.12459DOI Listing
June 2019

Complementary Role of P2 and Adenosine Receptors in ATP Induced-Anti-Apoptotic Effects Against Hypoxic Injury of HUVECs.

Int J Mol Sci 2019 Mar 22;20(6). Epub 2019 Mar 22.

Department of Pharmacology, E.A.3801, SFR CAP-santé, Reims University Hospital, 51, rue Cognacq-Jay, 51095 Reims CEDEX, France.

Background: Vascular endothelial injury during ischemia generates apoptotic cell death and precedes apoptosis of underlying tissues. We aimed at studying the role of extracellular adenosine triphosphate (ATP) on endothelial cells protection against hypoxia injury.

Methods: In a hypoxic model on endothelial cells, we quantified the extracellular concentration of ATP and adenosine. The expression of mRNA (ectonucleotidases, adenosine, and P2 receptors) was measured. Apoptosis was evaluated by the expression of cleaved caspase 3. The involvement of P2 and adenosine receptors and signaling pathways was investigated using selective inhibitors.

Results: Hypoxic stress induced a significant increase in extracellular ATP and adenosine. After a 2-h hypoxic injury, an increase of cleaved caspase 3 was observed. ATP anti-apoptotic effect was prevented by suramin, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), and CGS15943, as well as by selective A2A, A2B, and A3 receptor antagonists. P2 receptor-mediated anti-apoptotic effect of ATP involved phosphoinositide 3-kinase (PI3K), extracellular signal-regulated kinases (ERK1/2), mitoK, and nitric oxide synthase (NOS) pathways whereas adenosine receptor-mediated anti-apoptotic effect involved ERK1/2, protein kinase A (PKA), and NOS.

Conclusions: These results suggest a complementary role of P2 and adenosine receptors in ATP-induced protective effects against hypoxia injury of endothelial. This could be considered therapeutic targets to limit the development of ischemic injury of organs such as heart, brain, and kidney.
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http://dx.doi.org/10.3390/ijms20061446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470483PMC
March 2019

Glibenclamide oral suspension: Suitable and effective in patients with neonatal diabetes.

Pediatr Diabetes 2019 05 21;20(3):246-254. Epub 2019 Feb 21.

Pediatric diabetes and endocrinology, Necker Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.

Background: Results of genetic have led to off-label glibenclamide treatment in patients with neonatal diabetes (NDM) because of potassium channel mutations. No pediatric form of glibenclamide was available. Glibenclamide was designated an orphan drug designation for NDM and a suspension was developed. As a part of the pediatric plan investigation, we assessed its acceptability, efficiency, and safety.

Methods: In this Phase II, prospective, non-randomized, single-center study, patient received glibenclamide tablets for 1 month then the suspension for 3 months. We assessed acceptability using hedonic scales and patient questionnaires, effectiveness using glycated hemoglobin (HbA1C) assays and safety based on hypo and hyperglycemia, and other adverse events.

Results: We included 10 patients (0.1-16.2 years, 6 < 5 years) were included. Younger patients preferred the suspension and older the tablets. All parents were satisfied with the ease of suspension administration. The parents of 5 of 6 younger children preferred the suspension over the tablets and kept it. Switching from tablets to suspension did not affect the excellent metabolic control (median HbA1c change, -0.40%, [-1.3% to 0.5%] P = 0.08). Median frequencies of hypoglycemia and hyperglycemia were less than 5% of routine blood glucose assays and were similar with both dosage forms. Two patients each experienced one episode of hypoglycemia below 35 mg/dL highlighting the need for dosage titration when switching from tablets to suspension. Transient and non-severe abdominal pain or diarrhea occurred in three patients. None of the patients discontinued the treatment.

Conclusion: The glibenclamide oral suspension Amglidia, the first anti-diabetic drug specifically developed for pediatric patients, is acceptable, effective, and safe in patients with NDM (NCT02375828).

Clinical Trial Registration: Glibentek in Patients with Neonatal Diabetes Secondary to Mutations in K + -ATP Channels, clinicaltrials.gov, NCT02375828, https://clinicaltrials.gov/ct2/show/NCT02375828.
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http://dx.doi.org/10.1111/pedi.12823DOI Listing
May 2019

The IL-1β Antibody Gevokizumab Limits Cardiac Remodeling and Coronary Dysfunction in Rats With Heart Failure.

JACC Basic Transl Sci 2017 Aug 28;2(4):418-430. Epub 2017 Aug 28.

INSERM U1096, Rouen, France.

This study reports preclinical data showing that the interleukin (IL)-1β modulation is a new promising target in the pathophysiological context of heart failure. Indeed, in nondiabetic Wistar and diabetic Goto-Kakizaki rats with chronic heart failure induced by myocardial infarction, administration of the IL-1β antibody gevokizumab improves 'surrogate' markers of survival (i.e., left ventricular remodeling, hemodynamics, and function as well as coronary function). However, whether IL-1β modulation per se or in combination with standard treatments of heart failure improves long-term outcome in human heart failure remains to be determined.
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http://dx.doi.org/10.1016/j.jacbts.2017.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034492PMC
August 2017

Mineralocorticoid receptor antagonism improves diastolic dysfunction in chronic kidney disease in mice.

J Mol Cell Cardiol 2018 08 6;121:124-133. Epub 2018 Jul 6.

Institut National de la Santé et de la Recherche Médicale Inserm U1138, Cordeliers Institute, Paris VI-University, Paris, France.

Managing the cardiovascular complications of renal failure is a major therapeutic challenge in clinical practice. Mineralocorticoid Receptor (MR) blockade is a highly effective strategy for the management of heart failure, but the use of MR antagonists (MRA) is limited by their side effects rendering them contraindicated in patients with renal failure. Finerenone is a new non-steroidal MRA that shows fewer hyperkaliaemic events than the traditional steroidal MRAs and could therefore represent an alternative to these molecules in patients with damaged kidney function. The aim of this study is to characterize the effects of Finerenone on the cardiac complications of renal failure in a mouse model of chronic kidney disease (CKD). CKD was induced by subtotal nephrectomy (Nx), and finerenone was administered at a low dose (2.5 mg/kg/d) from week 4 to week 10 post-Nx. Cardiac function was assessed by echocardiography and invasive hemodynamics while cardiac fibrosis was measured by Sirius Red staining. Renal failure induced cardiac systolic and diastolic dysfunctions in the untreated CKD mice, as well as minor changes on cardiac structure. We also observed alterations in the phosphorylation of proteins playing key roles in the calcium handling (Phospholamban, Calmodulin kinase II) in these mice. Finerenone prevented most of these lesions with no effects on neither the renal dysfunction nor kaliemia. The benefits of finerenone suggest that activation of MR is involved in the cardiac complication of renal failure and strengthen previous studies showing beneficial effects of MRA in patients with CKD.
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http://dx.doi.org/10.1016/j.yjmcc.2018.06.008DOI Listing
August 2018

Alteration in the availability of epoxyeicosatrienoic acids contributes with NO to the development of endothelial dysfunction in conduit arteries during aging.

Atherosclerosis 2018 08 19;275:239-245. Epub 2018 Jun 19.

Department of Pharmacology, CHU de Rouen, 76000, Rouen, France; INSERM U1096, Normandie University, UNIROUEN, 76000, Rouen, France; Centre d'Investigation Clinique (CIC)-INSERM 1404, CHU de Rouen, 76000, Rouen, France. Electronic address:

Background And Aims: The mechanisms involved in endothelial dysfunction in humans during aging are largely unknown at the level of conduit arteries. We aimed to asses the role of NO and CYP450 epoxygenases-derived epoxyeicosatrienoic acids (EETs) in the regulation of endothelium-dependent flow-mediated dilatation of conduit arteries during aging.

Methods: Radial artery diameter and mean wall shear stress were determined by echotracking coupled with Doppler in 83 subjects (19-71 years old) during a sustained flow increase induced by hand skin heating, with the brachial infusion of saline or NO-synthase and cytochrome P450 epoxygenase inhibitors (L-NNMA and fluconazole respectively). Local blood sampling was performed for the quantification of NO metabolite nitrite and EETs.

Results: The magnitude of flow-mediated dilatation was independently and negatively correlated with age, baseline artery diameter and systolic blood pressure, and positively correlated with the increase in shear stress induced by heating. There was an increase in nitrite level during heating until the age of 35-40 years, which declined thereafter. However, the inhibitory effect of L-NMMA on flow-mediated dilatation progressively decreased during aging, demonstrating a decrease in functional NO availability. Moreover, aging progressively reduced the increase in EET level during heating as well as the inhibitory effect of fluconazole on flow-mediated dilatation.

Conclusions: These results show that aging impairs the availability of EETs and NO and epoxyeicosatrienoic acids in peripheral conduit arteries, contributing to the development of endothelial dysfunction.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.06.865DOI Listing
August 2018

Protein tyrosine phosphatase 1B inactivation limits aging-associated heart failure in mice.

Am J Physiol Heart Circ Physiol 2018 06 23;314(6):H1279-H1288. Epub 2018 Mar 23.

Normandie University UNIROUEN, Institut National de la Santé et de la Recherche Médicale U1096 , Rouen , France.

We have previously shown that protein tyrosine phosphatase 1B (PTP1B) inactivation in mice [PTP1B-deficient (PTP1B) mice] improves left ventricular (LV) angiogenesis, perfusion, remodeling, and function and limits endothelial dysfunction after myocardial infarction. However, whether PTP1B inactivation slows aging-associated cardiovascular dysfunction remains unknown. Wild-type (WT) and PTP1B mice were allowed to age until 18 mo. Compared with old WT mice, in which aging increased the LV mRNA expression of PTP1B, old PTP1B mice had 1) reduced cardiac hypertrophy with decreased LV mRNA levels of hypertrophic markers and atrial and brain natriuretic peptides, 2) lower LV fibrosis (collagen: 16 ± 3% in WT mice and 5 ± 3% in PTP1B mice, P < 0.001) with decreased mRNA levels of transforming growth-factor-β and matrix metalloproteinase-2, and 3) higher LV capillary density and lower LV mRNA level of hypoxic inducible factor-1α, which was associated over time with a higher rate of proangiogenic M2 type macrophages and a stable LV mRNA level of VEGF receptor-2. Echocardiography revealed an age-dependent LV increase in end-diastolic volume in WT mice together with alterations of fractional shortening and diastole (transmitral Doppler E-to-A wave ratio). Invasive hemodynamics showed better LV systolic contractility and better diastolic compliance in old PTP1B mice (LV end-systolic pressure-volume relation: 13.9 ± 0.9 in WT mice and 18.4 ± 1.6 in PTP1B mice; LV end-diastolic pressure-volume relation: 5.1 ± 0.8 mmHg/relative volume unit in WT mice and 1.2 ± 0.3 mmHg/relative volume unit in PTP1B mice, P < 0.05). In addition, old PTP1B mice displayed a reduced amount of LV reactive oxygen species. Finally, in isolated resistance mesenteric arteries, PTP1B inactivation reduced aging-associated endothelial dysfunction (flow-mediated dilatation: -0.4 ± 2.1% in WT mice and 8.2 ± 2.8% in PTP1B mice, P < 0.05). We conclude that PTP1B inactivation slows aging-associated LV remodeling and dysfunction and reduces endothelial dysfunction in mesenteric arteries. NEW & NOTEWORTHY The present study shows that protein tyrosine phosphatase 1B inactivation in aged mice improves left ventricular systolic and diastolic function associated with reduced adverse cardiac remodeling (hypertrophy, fibrosis, and capillary rarefaction) and limits vascular endothelial dysfunction. This suggests that protein tyrosine phosphatase 1B inhibition could be an interesting treatment approach in age-related cardiovascular dysfunction.
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http://dx.doi.org/10.1152/ajpheart.00049.2017DOI Listing
June 2018

Population Pharmacokinetic-Pharmacodynamic Modeling of Ropivacaine in Spinal Anesthesia.

Clin Pharmacokinet 2018 09;57(9):1135-1147

Department of Pharmacology, EA3801, SFR CAP-Santé, Reims University Hospital, 51, rue Cognacq-Jay, 51095, Reims Cedex, France.

Background: Ropivacaine is frequently used in spinal anesthesia but the relationship between plasma concentrations and sensory block level remains unknown.

Objective: The aim of this study was to assess the relationship between plasma ropivacaine concentrations and effects during spinal anesthesia.

Methods: Sixty patients aged between 18 and 82 years were included in this study after providing written informed consent. Patients were randomly assigned to receive intrathecal administration of ropivacaine 15, 20 or 25 mg. Blood samples were drawn to determine ropivacaine concentrations, and sensory blockade was assessed using pinprick testing. Ropivacaine plasma concentrations and sensory block level were analyzed using a nonlinear mixed-effects modeling approach with Monolix 4.2.2. Uncertainty of parameters was estimated by bootstrapping.

Results: Overall, 216 plasma ropivacaine values and 407 sensory block-related data were available for pharmacokinetic-pharmacodynamic (PK-PD) model evaluation. A two-compartment open model connected to a spinal compartment was selected to describe the PKs of ropivacaine. Sensory block modeling was performed using a sigmoid E model assuming an equilibration delay between the amount in the depot or spinal compartment and at the effect site. Using multiple linear regression analysis, we were able to demonstrate the importance of dose, age and weight as major predictors of sensory block-level kinetics.

Conclusions: This first population PK-PD model for ropivacaine in spinal anesthesia confirms the relationship between plasma ropivacaine concentrations and effect. We also clarify the relationship between the spread of sensory block level and dose, age and, for the first time, weight.

Study Registration: This study was approved by the Reims University Hospital Ethics Committee (protocol: PHRC-2005; registered at Agence Nationale de Sécurité du Médicament et des Produits de Santé ANSM: D60890). This was an open, prospective, monocentric study conducted in the University Hospital of Reims (France).
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http://dx.doi.org/10.1007/s40262-017-0617-2DOI Listing
September 2018