Lionel Tortolano

Brain and Plasma Riluzole Pharmacokinetics: Effect of Minocycline Combination

PURPOSEnamyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by the loss of motorneurons. The only drug approved is riluzole. Minocycline is an antibiotic with numerous neuroprotective properties. riluzole and minocycline were given to an animal model of ALS and had beneficial effect on the disease. The combination was then tested in humans in phase II and phase III studies with less beneficial effects and a faster decline of the disease in the group treated with minocycline. In a previous study, we showed that riluzole is transported out of the brain by the P-glycoprotein at the blood-brain barrier level.nnnMETHODSnin this work, we studied in CF1 mice, the plasmatic and cerebral pharmacokinetics of riluzole combined or not with minocycline.nnnRESULTSnour results showed that the kinetics of riluzole are not linear with dose, but that cerebral AUC0-infinity increase proportionally with plasmatic AUC0-infinity. At the dose of 10 mg/kg, the cerebral AUC0-infinity /plasmatic AUC0-infinity ratio was 4.6 in mdr1a (-/-) mice and 2.4 in mdr1a (+/+) mice. The combination of minocycline (170 mg/kg) and riluzole (10 mg/kg) induced a 2 fold increase in the cerebral AUC0-infinity of riluzole and induced a neuromuscular toxicity in mice. This effect of minocycline was not found at low concentration (10 mg/kg of minocycline).nnnCONCLUSIONSnif our results are confirmed in humans, riluzole cerebral concentrations could be predicted by plasmatic concentrations. Furthermore, the combination of high doses of minocycline with riluzole could induce neurological toxicity that lead to deceiving results in ALS clinical studies.

Interaction of intraocular lenses with fibronectin and human lens epithelial cells: Effect of chemical composition and aging.

The aim of this study is to investigate in vitro interactions between hydrophobic acrylate intraocular lenses (IOLs) and their biological environment. The influence of lens chemical composition and aging on fibronectin (FN) adsorption and on IOLs cytotoxicity on human lens epithelial cells was examined. Cytotoxicity of acrylate monomers used in IOLs manufacture was also investigated. Four different IOLs were included in the study: Acrysof(®), Tecnis(®), EnVista(®), and iSert(®). Implants were artificially aged in a xenon arc chamber to simulate 2 years of light exposure. Fibronectin adsorption on IOL surface was quantified using ELISA and correlated to surface roughness determined with AFM. Direct contact cytotoxicity was determined with the MTT assay and cell morphology was observed with light microscopy. Results showed that fibronectin adsorption did not differ significantly among IOLs, whatever their chemical composition. Moreover, aging conditions did not impact fibronectin adsorption. All IOLs were biocompatible even after applying 2-year aging conditions, with cell viability higher than 70%. Five acrylate monomers appeared to be toxic in the range of concentrations tested, but no monomer release from the IOLs could be detected during accelerated 2-year incubation with saline solution. This study did not reveal an influence of chemical composition and aging on protein adsorption and on biocompatibility.

Pemetrexed degradation by photocatalytic process: Kinetics, identification of transformation products and estimation of toxicity

This study employed a UV-A/visible/TiO2 system to investigate the degradation of pemetrexed, an antifolate agent used in chemotherapy. The laboratory-scale method employed a photostability chamber that could be used to study multiple samples. Reversed-phase HPLC coupled with high-resolution ESI-LTQ-Orbitrap mass spectrometry was used to determine the transformation products (TPs) of PEME. Based on the identified TPs and existing chemical knowledge, the mechanism of degradation of the target compound was proposed. Concentrations were monitored as a function of time, and the degradation kinetics were compared. The structures of seven TPs, four of which have not been described to date, were proposed. Most of the TPs stemmed from OH radical additions to the dihydropyrrole moiety and oxidative decarboxylation of the glutamate residue. Based on the elucidated structures, a computational toxicity assessment was performed, showing that the TPs with higher log D values than the parent compound are more toxic than the PEME itself. To support these findings, the toxicities of irradiated samples on Vibrio fischeri were monitored over time. The experimental results corresponded well with the results of previous computational studies.

Biocompatibility assessment of cyclic olefin copolymers: Impact of two additives on cytotoxicity, oxidative stress, inflammatory reactions, and hemocompatibility

This work reports the biocompatibility evaluation of cyclic olefin copolymers (COC) as candidates for implantable medical devices. The focus was to establish the influence of two major additives (antioxidant and lubricant) on the overall biocompatibility. The cytotoxicity was evaluated according to ISO 10993-5 guidelines using L929 fibroblasts, HUVEC, and THP-1-derived macrophages. Oxidative stress (ROS, GSH/GSSG, and SOD analysis) and pro-inflammatory cytokines (Il-6 and TNF-α secretion) were quantified using THP-1 cells in direct contact with films. Hemocompatibility was assessed through haemolysis testing, dynamic blood coagulation, platelet adhesion, and activation (membranous P-selectin expression). Results show that the different types of COC have successfully passed the in vitro biocompatibility tests. The presence of antioxidant induces however a slight decrease in ROS production in correlation with a high SOD activity and a modification in blood coagulation profile probably linked to antioxidant recrystallization phenomenon on the surface of COC. The lubricant presence reduced haemolysis, fibrinogen adhesion, and platelet activation. Surface nanotopography of COC highlights different types of needles and globules according to the present additive. Those primary results indicate that COC are promising biomaterial. However, additives influenced some biological parameters pointing out the necessity of a global approach of risk analysis for biocompatibility evaluation.

RP-HPLC detection and dosage method for acrylic monomers and degradation products released from implanted medical devices.

Acrylic copolymers are useful in medical therapeutics. As in dental implants or intraocular lenses, acrylics are present in many medical devices or drug adjuvants. Industrial using of acrylics is still important in painting or textile manufacturing. Scientific research background has proved that acrylic suffer for depolymerized and cross-linking mechanisms under heating and photo-oxidative conditions. Those aging processes could lead to release of unreacted monomers and degradation products. We developed a new RP-HPLC method with good resolution, recovery, linearity, detection and quantification limits that is efficient for acrylic monomers quantification in in vitro and in vivo saline solution matrices. This method allows the detection of copolymer and medical devices degradation products too. Both the limit of quantification and the limit of detection for monomers and degradation products are above cytotoxic concentrations for human epithelial cells. Those biological results confirm the interest of the method for dosage of unreacted acrylics after polymerization and for the research of degradation products in body fluids as aqueous humor.

Computerized pediatric oncology prescriptions review by pharmacist: A descriptive analysis and associated risk factors

Systematic prescription analyses by clinical pharmacists result in pharmacist interventions (PIs) to reduce prescription errors and improve medication safety. PIs are particularly critical in oncology, because antineoplastic drugs are highly toxic with low therapeutic indexes especially in a pediatric population. The aim of this study is to describe PIs in a pediatric oncology department and to identify potential risk factors associated with prescription errors.

Permeability of expander breast implants: In vitro and in vivo analyses

INTRODUCTIONnThe biocompatibility of the polysiloxane breast implant has been studied moderately. The aging of these implants due to lipid penetration and the release of polymerization impurities, such as Platine or octamethylcyclotetrasiloxane (named D4), has already been documented. Since these studies, manufacturing procedures have been improved; thus, the security of breast implants has also improved. Although polymerization and the choice of monomer influence the shell properties, few studies have compared these together in breast implants. Our study compares the permeability and mechanical resistance of 3 breast expander shells after in vivo and in vitro aging.nnnRESULTSnIn vitro, all tested shells quickly sorbed linear molecules, such as fatty acids, and released siloxane impurities. The penetration of a molecule with steric hindrance, such as cholesterol, is slower. Allergan shells have the highest rates of molecule sorption and siloxane release. In vivo, after implantation, Allergan shells lost their initial mechanical properties over time. This observation was not found for mentor shells. For all brands, many biological molecules penetrate the shells, among which cholesterol and fatty acids are always present.nnnDISCUSSIONnThe aging of polysiloxane shells depends on the sorption of many biological molecules and the release of siloxane impurities. The siloxanes are impurities and / or degradation products that are due to aging. Moreover, according to our results, the shells act as matrices that separate molecules according to their chemical and physical properties.nnnCONCLUSIONnNot all polysiloxane expander shells have the same properties during aging. The manufacturing procedures and the choice of siloxane monomers are the two most probative factors that explain the observed differences.