Valérie Sautou

Migrability of PVC plasticizers from medical devices into a simulant of infused solutions.

Medical devices (MD) for infusion and artificial nutrition are essentially made of plasticized PVC. The plasticizers in the PVC matrix can leach out into the infused solutions and may enter into contact with the patients. In order to assess the risk of patient exposure to these plasticizers we evaluated the migration performance of DEHP, DEHT, DINCH, and TOTM using a model adapted to the clinical use of the MDs. Each PVC tubing sample was immersed in a simulant consisting of a mixture of ethanol/water (50/50v/v) at 40°C and migration tests were carried out after 24h, 72h, and 10 days.DEHP had the highest migration ability, which increased over time. The amount of TOTM released was more than 20 times less than that of DEHP, which makes it an interesting alternative. DEHT is also promising, with a migration level three times smaller than DEHP. However, the migration ability of DINCH was similar to DEHP, with the released amounts equaling 1/8th of the initial amount in the tubing after 24h of contact. Taking into account the available toxicological data, TOTM and DEHT appear to be of particular interest. However, these data should be supplemented and correlated with clinical and toxicological studies on plasticizers and their metabolites.

Analysis of PVC plasticizers in medical devices and infused solutions by GC–MS

In 2008, di-(2-ethylhexyl) phthalate (DEHP), was categorized as CMR 1B under the CLP regulations and its use in PVC medical devices (MD) was called into question by the European authorities. This resulted in the commercialization of PVC MDs plasticized with the DEHP alternative plasticizers tri-octyl trimellitate (TOTM), di-(2-ethylhexyl) terephthalate (DEHT), di-isononyl cyclohexane-1,2-dicarboxylate (DINCH), di-isononyl phthalate (DINP), di-(2-ethylhexy) adipate (DEHA), and Acetyl tri-n-butyl citrate (ATBC). The data available on the migration of these plasticizers from the MDs are too limited to ensure their safe use. We therefore developed a versatile GC-MS method to identify and quantify both these newly used plasticizers and DEHP in MDs and to assess their migration abilities in simulant solution. The use of cubic calibration curves and the optimization of the analytical method by an experimental plan allowed us to lower the limit of plasticizer quantification. It also allowed wide calibration curves to be established that were adapted to this quantification in MDs during migration tests, irrespective of the amount present, and while maintaining good precision and accuracy. We then tested the developed method on 32 PVC MDs used in our hospital and evaluated the plasticizer release from a PVC MD into a simulant solution during a 24h migration test. The results showed a predominance of TOTM in PVC MDs accompanied by DEHP (<0.1% w/w), DEHT, and sometimes DEHA. The migration tests showed a difference in the migration ability between the plasticizers and a non-linear kinetic release.

Managing drug–drug interactions with new direct-acting antiviral agents in chronic hepatitis C

Several direct‐acting antiviral agents (DAAs) have marketing authorization in Europe and in the USA and have changed the landscape of hepatitis C treatment: each DAA has its own metabolism and drug–drug interactions (DDIs), and managing them is a challenge. To compile the pharmacokinetics and DDI data of the new DAA and to provide a guide for management of DDI. An indexed MEDLINE search was conducted using the keywords: DAA, hepatitis C, simeprevir, daclatasvir, ledipasvir, sofosbuvir, 3D regimen (paritaprevir/ritonavir, ombitasvir, dasabuvir), DDI and pharmacokinetics. Data were also collected from hepatology, and infectious disease and clinical pharmacology conferences abstracts. Food can play a role in the absorption of DAAs. Most of the interactions are linked to metabolism (cytochrome P450‐3 A4 [CYP3A4]) or hepatic and/or intestinal transporters (organic anion‐transporting polypeptide and P‐glycoprotein [P‐gp]). To a lesser extent other pathways can be involved such as breast cancer resistance protein transporter or UDP‐glucuronosyltransferase metabolism. DDI are more likely to occur with 3D regimen, daclatasvir, simeprevir and ledipasvir, as they are all both substrates and inhibitors of P‐gp and/or CYP3A4, than with sofosbuvir. They can increase concentrations of coadministered drugs and their concentrations may be influenced by P‐gp or CYP3A4 inducers or inhibitors. Overdosage or low dosage can be encountered with potent inducers or inhibitors of CYP3A4 or drugs with a narrow therapeutic range. The key to interpret DDI data is a good understanding of the pharmacokinetic profiles of the drugs involved. Their ability to inhibit CYP450‐3A4 and transporters (hepatic and/or intestinal) can have significant clinical consequences.

A chemometric approach to elucidate the parameter impact in the hyphenation of evaporative light scattering detector to supercritical fluid chromatography.

The aim of this work was to elucidate the effects of parameters influencing the evaporative light scattering detector (ELSD) response when it was coupled to supercritical fluid chromatography (SFC). Phthalates, currently used as plasticizers in medical devices, were selected as model compounds. The configuration of the hyphenation setup was firstly optimized and shown that both peak efficiency and sensitivity were improved by connecting the ELSD to the SFC before the back pressure regulator (BPR). By using a tee-junction which splits the flow after the PDA towards the collect fraction (or waste) and the ELSD, this instrument configuration has the advantage to be applicable for small-scale preparative SFC. The impacts of other parameters such as mobile phase composition and flow rate, outlet pressure, column oven temperature and ELSD drift tube temperature on the ELSD signal were evaluated using a chemometric approach. First, it was demonstrated that a classical mobile phase composed of CO2-methanol 90:10 (v/v) was suitable to obtain great nebulization efficiency. The flow rate of the eluent was the second main effect factor. The setting must be as low as possible to avoid the loss of large particle size in the drift tube resulting in a loss of signal intensity. Concerning the outlet pressure, the configuration of the setup between SFC and ELSD requires a setting as high as possible to limit the partial liquid-vapor separation of the mobile phase in the restrictor tube. Finally, due to the low quantity of solvent which must be evaporated in the detector, a drift tube temperature of 25 °C is suitable for the hyphenation of ELSD to SFC. In the optimized conditions, the proposed SFC/ELSD method could be suitable to quantify plasticizers in medical devices.

The analgesic effects of a bilateral sternal infusion of ropivacaine after cardiac surgery.

Background and Objectives The aim of this study was to assess the effects of a continuous postoperative administration of local anesthetic through 2 catheters placed deeply under fascia at the lateral edges of the sternum, close to the emergence of the intercostal nerves. We focused on pain during mobilization, as this aspect is likely to interact with postoperative morbidity. Methods Forty adult patients scheduled for open heart surgery with sternotomy were included in this randomized, placebo-controlled, double-blind study. A continuous fixed-rate infusion of 4 mL/hr of 0.2% ropivacaine or normal saline was administered during the first 48 postoperative hrs. All patients received acetaminophen and self-administered morphine. The efficacy outcomes were as follows: pain score during standardized mobilization and at rest; morphine consumption; spirometry and arterial blood gases; postoperative rehabilitation criteria, and patient satisfaction. Total ropivacaine plasma level was monitored throughout the study. Results Pain scores were lower in the ropivacaine group during mobilization (P = 0.0004) and at rest (P = 0.0006), but the analgesic effects were mostly apparent during the second day after surgery, with a 41% overall reduction in movement-evoked pain levels. The bilateral sternal block also reduced morphine consumption. It improved the patients’ satisfaction and rehabilitation, but no effects were noted on respiratory outcomes. No major adverse effect due to the treatment occurred, but the ropivacaine plasma level was greater than 4 mg/L in 1 patient. Conclusions This technique may find a role within the framework of multimodal analgesia after sternotomy, although further confirmatory studies are needed.

Quantification of five plasticizers used in PVC tubing through high performance liquid chromatographic-UV detection.

Searching for alternatives to di-(2-ethylhexyl)-phthalate, a plasticizer that has been widely used in the manufacturing of PVC medical devices, has become a major challenge since a European regulation underlined some clinical risks. The aim of this study is to develop an HPLC-UV method to quantify the currently used alternative plasticizers to DEHP. Five plasticizers, acetyl tributyl citrate, di-(2-ethylhexyl)-phthalate, di-(ethylhexyl)-terephthalate, di-isononyl-1,2-cyclohexane-dicarboxylate, and trioctyl trimellitate, were separated on a C8 stationary phase (2.6 μm, 100 mm × 4.6mm) under gradient elution in 13 min. They were detected at 221 nm leading to a quantification threshold from 0.3 to 750 μg/mL as a function of the plasticizer. Within-day and between-day precisions were inferior to 0.9% and 18%, respectively. The assays were validated according to the accuracy profile method. Plasticizers were extracted from PVC-tubing by dissolving PVC in THF then precipitating it in methanol with a yield of over 90% for each plasticizer. This assay could feasibly be used to quantify plasticizers in PVC medical devices.

Comparison of high-performance liquid chromatography and supercritical fluid chromatography using evaporative light scattering detection for the determination of plasticizers in medical devices.

Recently, interest in supercritical fluid chromatography (SFC) has increased due to its high throughput and the development of new system improving chromatographic performances. However, most papers dealt with fundamental studies and chiral applications and only few works described validation process of SFC method. Likewise, evaporative light scattering detection (ELSD) has been widely employed in liquid chromatography but only a few recent works presented its quantitative performances hyphenated with SFC apparatus. The present paper discusses about the quantitative performances of SFC-ELSD compared to HPLC-ELSD, for the determination of plasticizers (ATBC, DEHA, DEHT and TOTM) in PVC tubing used as medical devices. After the development of HPLC-ELSD, both methods were evaluated based on the total error approach using accuracy profile. The results show that HPLC-ELSD was more precise than SFC-ELSD but lower limits of quantitation were obtained by SFC. Hence, HPLC was validated in the ± 10% acceptance limits whereas SFC lacks of accuracy to quantify plasticizers. Finally, both methods were used to determine the composition of plasticized-PVC medical devices. Results demonstrated that SFC and HPLC both hyphenated with ELSD provided similar results.

Influence of Lipid Type on Bis (2-ethylhexyl)phthalate (DEHP) Leaching From Infusion Line Sets in Parenteral Nutrition

BACKGROUND Bis(2-ethylhexyl)phthalate (or DEHP) is widely used in polyvinyl chloride (PVC) tubings for its good plasticizing properties. Because it is not covalently bound to the plastic matrix, it is able to escape from PVC during the infusion of the lipid emulsions used in parenteral nutrition (PN). This creates a vector through which it can enter into contact with the patient via the nutrition admixtures infused. This study was designed to assess the potential role of the type of lipids used in PN admixtures on the quantity of DEHP leached out from PVC-based tubings. METHODS PVC-based infusion lines, 6 commercially available lipid emulsions, and their oil base components were left in direct contact, and the amount of DEHP leached was measured by liquid chromatography. RESULTS After a 24-hour exposure period, DEHP migration varied significantly (P = .0000152) according to lipid type. The olive oil-based emulsion Clinoleic leached the most DEHP (65.8 µg/mL intravenous fat emulsion), followed by the fish oil-based emulsion Omegaven (37.8 µg/mL). The soybean oil-based emulsions Intralipid, Medialipide, Lipidem, and Structolipid showed comparable performances, with DEHP leaching rates into the emulsion measured at 27.3, 27.8, 23.6, and 19.6 µg/mL, respectively. Results from the same experiments run on pure-form oils (soybean oil, olive oil, coconut oil, and cod liver oil) confirmed the influence of lipid type on DEHP leaching. CONCLUSION The major DEHP leaching caused by olive oil-based emulsions raises cause for concern because DEHP presents distinctive toxic effects, including an increased risk of cholestasis.

Fabrication of Acrylonitrile-Butadiene-Styrene Nanostructures with Anodic Alumina Oxide Templates, Characterization and Biofilm Development Test for Staphylococcus epidermidis

Medical devices can be contaminated by microbial biofilm which causes nosocomial infections. One of the strategies for the prevention of such microbial adhesion is to modify the biomaterials by creating micro or nanofeatures on their surface. This study aimed (1) to nanostructure acrylonitrile-butadiene-styrene (ABS), a polymer composing connectors in perfusion devices, using Anodic Alumina Oxide templates, and to control the reproducibility of this process; (2) to characterize the physico-chemical properties of the nanostructured surfaces such as wettability using captive-bubble contact angle measurement technique; (3) to test the impact of nanostructures on Staphylococcus epidermidis biofilm development. Fabrication of Anodic Alumina Oxide molds was realized by double anodization in oxalic acid. This process was reproducible. The obtained molds present hexagonally arranged 50 nm diameter pores, with a 100 nm interpore distance and a length of 100 nm. Acrylonitrile-butadiene-styrene nanostructures were successfully prepared using a polymer solution and two melt wetting methods. For all methods, the nanopicots were obtained but inside each sample their length was different. One method was selected essentially for industrial purposes and for better reproducibility results. The flat ABS surface presents a slightly hydrophilic character, which remains roughly unchanged after nanostructuration, the increasing apparent wettability observed in that case being explained by roughness effects. Also, the nanostructuration of the polymer surface does not induce any significant effect on Staphylococcus epidermidis adhesion.

Medical plastics : compatibility of alfentanil and propofol alone or mixed. Stability of the alfentanil-propofol mixture

This study concerns the respective compatibilities of propofol Diprivan® and alfentanil Rapifen® towards medical plastics during infusion (at different flow rates) and in static models. We also determined this compatibility when the two drugs were administered as a propofol/alfentanil 30/20 (V/V) mixture and we observed the stability of the association. The work was conducted under conditions consistent with the use of the drugs for hospital anesthesia. Propofol and alfentanil were analysed by high performance liquid chromatography (HPLC). Propofol concentration decreased significantly when infused slowly (1 ml/h) for 6 h through PVC tubing. However, at the usual flow rate (10 ml/h), no significant difference was observed. Variations in alfentanil concentration never exceeded 10% (theoretical tolerated limit) at either flow rate of infusion (1 or 10 ml/h). Interrupting infusion for 2 h had no effects on the stability of propofol, and induced no significant loss in alfentanil concentration. The stability was always lower with the propofol/alfentanil mixture than with the two drugs separately.