Stéphanie Rolin

Effects of SiC nanoparticles orally administered in a rat model: Biodistribution, toxicity and elemental composition changes in feces and organs

BACKGROUND Silicon carbide (SiC) presents noteworthy properties as a material such as high hardness, thermal stability, and photoluminescent properties as a nanocrystal. However, there are very few studies in regard to the toxicological potential of SiC NPs. OBJECTIVES To study the toxicity and biodistribution of silicon carbide (SiC) nanoparticles in an in vivo rat model after acute (24h) and subacute (28days) oral administrations. The acute doses were 0.5, 5, 50, 300 and 600mg·kg(-1), while the subacute doses were 0.5 and 50mg·kg(-1). RESULTS SiC biodistribution and elemental composition of feces and organs (liver, kidneys, and spleen) have been studied by Particle-Induced X-ray Emission (PIXE). SiC and other elements in feces excretion increased by the end of the subacute assessment. SiC did not accumulate in organs but some elemental composition modifications were observed after the acute assessment. Histopathological sections from organs (stomach, intestines, liver, and kidneys) indicate the absence of damage at all applied doses, in both assessments. A decrease in the concentration of urea in blood was found in the 50mg·kg(-1) group from the subacute assessment. No alterations in the urine parameters (sodium, potassium, osmolarity) were found. CONCLUSION This is the first study that assesses the toxicity, biodistribution, and composition changes in feces and organs of SiC nanoparticles in an in vivo rat model. SiC was excreted mostly in feces and low traces were retrieved in urine, indicating that SiC can cross the intestinal barrier. No sign of toxicity was however found after oral administration.

Indanesulfonamides as carbonic anhydrase inhibitors and anticonvulsant agents: structure-activity relationship and pharmacological evaluation.

A small library of indanesulfonamides was screened for the inhibition of the human carbonic anhydrase (CA, EC 4.2.1.1) isoforms involved in neuronal excitation, that is, isoforms VII, XII and XIV. These CA isoforms are becoming interesting target for the design of agents useful for the treatment of epilepsy. The inhibition pattern of these indanesulfonamide compounds towards these three isoforms was excellent, with many nanomolar inhibitors detected (K(I)s in the range of 0.78-10 nM against hCA VII; 0.32-56 nM against hCA XII, and 0.47-1030 nM against hCA XIV, respectively). The maximal electroshock seizure (MES) test performed on mice showed a good anticonvulsant activity for some compounds which protected the mice against convulsions in the 50-62.5% range at a dose of 50 mg/kg. In parallel, the blood-brain barrier passive permeation of these sulfonamides was also estimated by using a computational approach.

Design, synthesis and biological evaluation of a sulfonylcyanoguanidine as thromboxane A2 receptor antagonist and thromboxane synthase inhibitor.

The synthesis and the structure of N‐isopropyl‐N′‐[2‐(3′‐methylphenylamino)‐5‐nitrobenzenesulfonyl] urea (14) was drawn from two thromboxane A2 receptor antagonists structurally related to torasemide. Compound 14 showed an IC50 value of 22 nm for the thromboxane A2 (TXA2) receptor of human washed platelets. Compound 14 prevented platelet aggregation induced by arachidonic acid (0.6 mm) and U‐46619 (1 μm) with an IC50 value of 0.45 and 0.15 μm, respectively. Moreover, 14 relaxed the rat isolated aorta and guinea‐pig trachea precontracted by U‐46619, a TXA2 agonist. Its efficacy (IC50) was 20.4 and 5.47 nm, respectively. Finally, 14 (1 μm) completely inhibited TXA2 synthase of human platelets. The pKa value and the crystallographic data of 14 were determined and used to propose an interaction model between the TXA2 antagonists related to torasemide and their receptor.

Validation of the calibrated thrombin generation test (cTGT) as the reference assay to evaluate the procoagulant activity of nanomaterials

Abstract We validated a preclinical toxicological screening assay and provided guidelines to evaluate the potential impact of nanoparticles (NPs) on blood coagulation. Five NPs with various physicochemical properties were studied using several existing methods of clotting times and thrombin generation assays in human normal pool plasma. In both recalcification clotting time (RCT) and calibrated thrombin generation test (cTGT), the NPs exhibited procoagulant activity (SiO2 ≥ SiC ≥ TiC > CuO > CB) but cTGT was more sensitive and relevant than RCT. Thus, the cTGT appears as a reference assay to investigate the nanoparticle (NP) procoagulant activity in human plasma. It should be used as the reference toxicity test for evaluating the effects of nanomaterials on coagulation cascade. In addition, we also showed that the use of the Pluronic F-108 dispersant and/or the sonication for the NP suspension preparation may mask their procoagulant activity and thus should be avoided.

Synthesis and pharmacological evaluation of a new targeted drug carrier system: β-Cyclodextrin coupled to oxytocin

Beta-cyclodextrin (beta-CD) was monofunctionalized into its carboxylic derivative and then conjugated to the N-side of oxytocin (OT), a nonapeptide involved in human behavior and myometrium contraction. On isolated rat myometrium, this conjugate (beta-CD-OT) partly preserves the contracting activity of OT (EC(50) = 0.40 microM vs 1.7 nM). Moreover, the contraction induced frequency is also lowered by beta-CD-OT. This novel hydrophilic targeted carrier could form a host-guest complex with prostaglandins and their derivatives used as labor inducers or with anticancer drugs used in cervix and endometrial cancer. This strategy can improve the solubility, the stability, and/or the biological activity of these drugs as well as reducing their side-effects.

BM-573 inhibits the development of early atherosclerotic lesions in Apo E deficient mice by blocking TP receptors and thromboxane synthase.

Atherosclerosis is the principal cause of mortality in industrialized countries. Its development is influenced by several mediators of which thromboxane A(2) (TXA(2)) and 8-iso-PGF(2α) have recently received a lot of attention. This study aimed to investigate the effect of a dual thromboxane synthase inhibitor and thromboxane receptor antagonist (BM-573) and ASA on lesion formation in apolipoprotein E-deficient mice. The combination of ASA and BM-573 was also studied. Plasma measurements demonstrated that the treatments did not affect body weight or plasma cholesterol levels. BM-573, but not ASA, significantly decreased atherogenic lesions as demonstrated by macroscopic analysis. Both treatments alone inhibited TXB(2) synthesis but only BM-573 and the combination therapy were able to decrease firstly, plasma levels of soluble intracellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) and secondly, the expression of these proteins in the aortic root of Apo E. These results were confirmed in endothelial cell cultures derived from human saphenous vein endothelial cells (HSVECs). In these cells, BM-573 also prevented the increased mRNA expression of ICAM-1 and VCAM-1 induced by U-46619 and 8-iso-PGF(2α). Our results show that a molecule combining receptor antagonism and thromboxane synthase inhibition is more efficient in delaying atherosclerosis in Apo E(-/-) mice than sole inhibition of TXA(2) formation.

Structure determination and comparison of BM567, a sulfonylurea, with terbogrel, two compounds with dual action, thromboxane receptor antagonism and thromboxane synthase inhibition

BM567, a sulfonylurea compound whose crystal structure is here discussed and terbogrel, are both thromboxane receptor antagonists and thromboxane synthase inhibitors. In this paper, their crystallographic and electronic structures are compared and lead to new synthesis prospects among the sulfonylurea series.

A comparison of six major platelet functional tests to assess the impact of carbon nanomaterials on platelet function: A practical guide

Abstract The study of the haemocompatibility of nanomaterials that could be in contact with blood (e.g. nanoparticle (NP)-based drug-delivery system) is of major importance. The primary objective of this study was to compare the ability of six platelet functional tests to assess the impact of NPs on platelet function. The secondary objective was to determine an accurate and reliable screening test to measure the potential impact of NPs on primary haemostasis whatever their physicochemical properties. Four types of carbon NPs (carbon black, fullerenes, single-walled carbon nanotubes and multi-walled carbon nanotubes) were investigated on six platelet function tests: light transmission aggregometry, whole-blood impedance aggregometry, platelet function analyser-100 (PFA-100®) and Cone-and-Plate(let) analyser (Impact-R®), transmission- and field emission gun scanning electron microscopy (FEG-SEM). We considered that Impact-R® supported by FEG-SEM is the reference method to investigate the potential impact of NPs on platelet function.

A pharmacophore model for sulphonyl-urea (-cyanoguanidine) compounds with dual action, thromboxane receptor antagonists and thromboxane synthase inhibitors.

A 3D pharmacophore model was developed for original sulphonyl-urea (-cyanoguanidine) compounds and known molecules which behave both as thromboxane receptor antagonists and as thromboxane synthase inhibitors. Five recognition sites appear to be essential for this dual activity: two hydrogen bond acceptors, an anionic site, a hydrophobic group and an aromatic ring. Such a model could be used to design new leads possessing the same pharmacological profile and to improve the activity of our compounds.

Cardiovascular haemodynamics and ventriculo-arterial coupling in an acute pig model of coronary ischaemia-reperfusion

Although reperfusion after coronary occlusion is mandatory for myocardial salvage, reperfusion may trigger a cascade of harmful events (reperfusion injury) adding to myocardial injury. We investigated effects of reperfusion on left ventricular (LV) haemodynamics and ventriculo‐arterial (VA) coupling in pigs following acute myocardial ischaemia induced by coronary artery occlusion. Experiments were performed in six animals, with measurements of cardiac and arterial function at baseline, after 60 min of ischaemia (T60) and after 2 (T180) and 4 h of reperfusion (T300). Ventriculo‐arterial coupling was assessed using the ventriculo‐arterial elastance ratio of paper, as well as using a ‘stiffness coupling’ and ‘temporal coupling’ index. Reperfusion following ischaemia (T180 versus T60) induced a progressive decline in cardiovascular function, evidenced by a decrease in mean arterial blood pressure, cardiac output and ejection fraction which was not restored at T300. Although reperfusion also induced an increase in slope of the end‐systolic pressure–volume relationship (ESPVR), the ESPVR curve shifted to the right, associated with a depression of contractile function. Histology demonstrated irreversible myocardial damage at T300. The ventriculo‐arterial elastance ratio and the ‘stiffness coupling’ index were unaffected throughout the protocol, but the ‘temporal coupling’ parameter indicated a relative shift between heart period and the time constant of the arterial system. It is unlikely that these alterations are attributable to ischaemic injury alone. The combination of both the stiffness and temporal coupling index may provide more information when studying ventriculo‐arterial coupling than the more commonly used ventricular end‐systolic stiffness/effection arterial elastance (Ees/Ea) ratio.