Comparative Study of Sorption Phenomena Between Three Medications and Syringes Made of Cyclic Olefin Copolymer or Polypropylene.

INTRODUCTION: Medical syringes are widely used in hospitals to store and administer drugs, and the contact time between the drugs and these syringes can vary from a few minutes to several weeks like for pharmaceutical preparations. The aim of this comparative study was to evaluate the potential sorption phenomena occurring between three drugs (paracetamol, diazepam and insulin aspart) and polypropylene syringes (PP) or syringes made of Cyclic Olefin Copolymer (COC). MATERIALS AND METHODS: 50 mL 3-part syringes made of either COC with crosslinked silicone on the barrel inner surface (COC-CLS) and a bromobutyl plunger seal, or PP lubricated with silicone oil (PP-SOL) with a polyisoprene plunger seal were used. RESULTS: COC-CLS syringes induced less sorption of diazepam and insulin than PP-SOL syringes and the plunger seal material seemed to be the main cause of these interactions. An alkalinization of the medications in contact with the PP-SOL syringes was observed. It could be caused by leachable compounds and should be investigated further. CONCLUSION: This work shows once again that it is essential to consider content-container interactions to help improve the safe use of parenteral drugs.

In vitro and in silico approach to study the hormonal activities of the alternative plasticizer tri-(2-ethylhexyl) trimellitate TEHTM and its metabolites.

Tri-(2-ethylhexyl) trimellitate (TEHTM) is a plasticizer for polyvinyl chloride (PVC) material used in medical devices. It is an alternative to di-(2-ethylhexyl) phthalate (DEHP), a well-known reprotoxic and endocrine disruptor. As plasticizers are known to easily migrate when in contact with fatty biological fluids, patient exposure to TEHTM is highly probable. However, there is currently no data on the potential endocrine-disrupting effects of its human metabolites. To evaluate the effects of TEHTM metabolites on endocrine activity, they were first synthesized and their effects on estrogen, androgen and thyroid receptors, as well as steroid synthesis, were investigated by combining in vitro and in silico approaches. Among the primary metabolites, only 4-MEHTM (4-mono-(2-ethylhexyl) trimellitate) showed agonist activities on ERs and TRs, while three diesters were TR antagonists at non-cytotoxic concentrations. These results were completed by docking experiments which specified the ER and TR isoforms involved. A mixture of 2/1-MEHTM significantly increased the estradiol level and reduced the testosterone level in H295R cell culture supernatants. The oxidized secondary metabolites of TEHTM had no effect on ER, AR, TR receptors or on steroid hormone synthesis. Among the fourteen metabolites, these data showed that two of them (4-MEHTM and 2/1-MEHTM) induced effect on hormonal activities in vitro. However, by comparing the concentrations of the primary metabolites found in human urine with the active concentrations determined in bioassays, it can be suggested that the metabolites will not be active with regard to estrogen, androgen, thyroid receptors and steroidogenesis-mediated effects.

Cyclodextrins Allow the Combination of Incompatible Vancomycin and Ceftazidime into an Ophthalmic Formulation for the Treatment of Bacterial Keratitis.

Ceftazidime (CZ) and vancomycin (VA) are two antibiotics used to treat bacterial keratitis. Due to their physical incompatibility (formation of a precipitate), it is not currently possible to associate both molecules in a single container for ophthalmic administration. We firstly characterized the incompatibility then investigated if 2-hydroxypropyl-beta (HPßCD) and 2-hydroxypropyl-gamma cyclodextrins (HPγCD) could prevent this incompatibility. The impact of pH on the precipitation phenomena was investigated by analysing the supernatant solution of the mixture using high performance liquid chromatography. A characterization of the inclusion of CZ with HPγCD using 1H nuclear magnetic resonance (NMR), and VA with HPßCD using 1H-NMR and a solubility diagram was performed. A design of experiment was built to determine the optimal conditions to obtain a formulation that had the lowest turbidity and particle count. Our results showed that VA and CZ form an equimolar precipitate below pH 7.3. The best formulation obtained underwent an in-vitro evaluation of its antibacterial activity. The impact of HPCDs on incompatibility has been demonstrated through the inclusion of antibiotics and especially VA. The formulation has been shown to be able to inhibit the incompatibility for pH higher than 7.3 and to possess unaltered antibacterial activity.

In vitro and in silico hormonal activity studies of di-(2-ethylhexyl)terephthalate, a di-(2-ethylhexyl)phthalate substitute used in medical devices, and its metabolites.

Plasticizers added to polyvinylchloride used in medical devices can be released into patients' biological fluids. The substitution of di-(2-ethylhexyl)phthalate (DEHP) by alternative plasticizers is essential but their safety must be demonstrated. DEHP, di-(2-ethylhexyl)terephthalate (DEHT) and their metabolites were investigated using level 2 Organization for Economic Co-operation and Development bioassays to screen for in vitro hormonal changes. Differences between the DEHP and DEHT metabolites were observed. Albeit weak, the hormonal activities of DEHT-derived metabolites, e.g., 5-OH metabolite of mono-(ethylhexyl)terephthalate (5-OH-MEHT), were detected and the results of docking experiments performed on estrogen receptor alpha and androgen receptor agreed with the biological results. A co-stimulation of human estrogen receptor alpha and human androgen receptor was also observed. With regard to steroidogenesis, a 16-fold increase in estrogen synthesis was measured with 5-OH-MEHT. Therefore, even if DEHT remains an interesting alternative to DEHP because of its low migration from medical devices, it seems important to verify that multi-exposed patients in neonatal intensive care units do not have urinary levels of oxidized metabolites, in particular 5-OH-MEHT, suggesting a potential endocrine-disrupting effect.

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.

Identification and quantification by 1H nuclear magnetic resonance spectroscopy of seven plasticizers in PVC medical devices.

Medical devices are generally made of polyvinyl chloride plasticized by six authorized plasticizers as alternatives to di-(2-ethylhexyl)-phthalate (DEHP) classified as reprotoxic class 1b. These are acetyl tri-n-butyl citrate (ATBC), di-(2-ethylhexy) adipate (DEHA), di-(2-ethylhexyl) terephthalate (DEHT), di-isononyl cyclohexane-1,2-dicarboxylate (DINCH), di-isononyl phthalate (DINP), and tri-octyl trimellitate (TOTM). The main objective of this study was to propose a new method using 1H NMR spectroscopy to determine and quantify these seven plasticizers in PVC sheets, standard infusion tubings, and commercially available medical devices. Two techniques were compared: dissolution in deuterated tetrahydrofuran and extraction by deuterated chloroform. Plasticizer 1H NMR spectra were very similar in both deuterated solvents; dissolution and extraction provided similar results. The sensitivity of this method enabled us to detect and quantify the presence of minor plasticizers in PVC. In nine commercially available samples, the major plasticizer was identified and quantified by 1H NMR. In six samples, one, two, or three minor plasticizers were identified and also quantified. DEHP was detected in only one tubing. NMR is therefore very convenient for studying plasticizers contained in medical devices. Only small quantities of solvents and sample are required. It is not necessary to dilute samples to enter a quantification range, and it is sufficiently sensitive to detect contaminants.

Exposure of hospitalised pregnant women to plasticizers contained in medical devices.

BACKGROUND: Medical devices (MDs) in polyvinyl chloride (PVC) are not a well-known source of exposure to plasticizers, in particular during pregnancy. Because of its toxicity, the di-(2-ethylhexyl) phthalate (DEHP) has been replaced by other plasticizers such as di (isononyl)-cyclohexane-1,2-dicarboxilic acid (DINCH), tri-octyltrimellitate (TOTM) and di-(isononyl) phthalate (DiNP). Our study aimed to quantify the plasticizers (DEHP and alternative plasticizers) contained in PVC medical devices used for hospitalised pregnant women and to describe which these MDs had been used (type, number, duration of exposure). METHODS: The plasticizers contained in the MDs used for daily care in the Obstetrics Department of a French University Hospital were extracted from PVC (after contact with a chloroform solution), identified and quantified by gas-chromatography-mass-spectrometry analysis. A total of 168 pregnant women hospitalised in the Obstetrics Department with at least one catheter were included in the observational study. The median number of MDs containing plasticizers used and the daily duration of exposure to the MDs were compared in three groups of pregnant women: "Pathology group" (women hospitalised for an obstetric disorder who did not give birth during this hospitalisation; n = 52), "Pathology and delivery group" (hospitalised for an obstetric disorder and who gave birth during this stay; n = 23) and "Delivery group" (admitted for planned or spontaneous delivery without obstetric disorder; n = 93). RESULTS: DiNP, TOTM and DINCH were the predominant plasticizers contained in the MDs at an amount of 29 to 36 g per 100 g of PVC. Women in the "Pathology group" (preterm labour or other pathology) were exposed to a median number of two MDs containing TOTM and one MD containing DiNP, fewer than those in the "Pathology and delivery group" (p < 0.05). Women in the "Pathology group" had a median exposure of 3.4 h/day to MDs containing DiNP and 8.2 h/day to MDs containing TOTM, longer than those in the "Delivery group" (p < 0.01). CONCLUSIONS: Our study shows that the medical management of pregnant women in a hospital setting entails exposure to MDs containing alternative plasticizers (DiNP, TOTM and DINCH).

Analysis of plasticizers in poly(vinyl chloride) medical devices for infusion and artificial nutrition: comparison and optimization of the extraction procedures, a pre-migration test step.

Medical devices (MDs) for infusion and enteral and parenteral nutrition are essentially made of plasticized polyvinyl chloride (PVC). The first step in assessing patient exposure to these plasticizers, as well as ensuring that the MDs are free from di(2-ethylhexyl) phthalate (DEHP), consists of identifying and quantifying the plasticizers present and, consequently, determining which ones are likely to migrate into the patient's body. We compared three different extraction methods using 0.1 g of plasticized PVC: Soxhlet extraction in diethyl ether and ethyl acetate, polymer dissolution, and room temperature extraction in different solvents. It was found that simple room temperature chloroform extraction under optimized conditions (30 min, 50 mL) gave the best separation of plasticizers from the PVC matrix, with extraction yields ranging from 92 to 100% for all plasticizers. This result was confirmed by supplemented Fourier transform infrared spectroscopy-attenuated total reflection (FTIR-ATR) and gravimetric analyses. The technique was used on eight marketed medical devices and showed that they contained different amounts of plasticizers, ranging from 25 to 36% of the PVC weight. These yields, associated with the individual physicochemical properties of each plasticizer, highlight the need for further migration studies.

Drug interactions and protease inhibitors used in the treatment of hepatitis C: how to manage?

PURPOSE: The first-generation protease inhibitors (PI) boceprevir and telaprevir combined with pegylated interferon have revolutionized the treatment of type-1 hepatitis C by increasing the rates of sustained virologic response. However, they induce drug interactions, and their clinical relevance is difficult to predict. This review compiles available data on drug-drug interactions (DDI) based on their pharmacokinetic and pharmacodynamic properties with the aim of assisting clinicians in managing DDI METHODS: PubMed, drug interaction databases and hepatology and infectious disease conference abstracts were systematically searched using the key search terms "interaction", "hepatitis C", "telaprevir" and "boceprevir". All known interactions were compiled and reclassified according to their pharmacokinetic and pharmacodynamic mechanisms. The state of knowledge of interaction mechanisms are reported and a therapeutic approach is proposed. RESULTS: Boceprevir and telaprevir are both substrates and potent inhibitors of cytochrome P450 3A4 and the drug transporter P-glycoprotein. They induce overdosage but can sometimes decrease the effect of other drugs by inducing other cytochromes. Overdosage or low dosage mainly affects drugs with a narrow therapeutic range, such as immunosuppressants or antiretrovirals. The distribution and elimination of PI are unaffected by interactions. In terms of pharmacodynamic interactions, PI can trigger drug-induced QT interval prolongation, which means that clinicians should manage such risk factors as potassium/magnesium levels or avoid other QT-prolonging drugs. CONCLUSIONS: Management of hepatitis C therapy is complex. The key to interpreting DDI data is a solid understanding of the pharmacokinetic and pharmacodynamic profiles of the drugs involved. Their ability to inhibit cytochrome P450 3A4 and prolong the QT interval can have significant clinical consequences. This review provides a practical guide to the safe and effective management of therapy with boceprevir and telaprevir.

A systematic review comparing the safety, cost and carbon footprint of disposable and reusable laparoscopic devices.

INTRODUCTION: The objective of this systematic review of the literature is to compare a selection of currently utilized disposable and reusable laparoscopic medical devices in terms of safety (1st criteria), cost and carbon footprint. MATERIAL AND METHODS: A search was carried out on electronic databases for articles published up until 6 May 2022. The eligible works were prospective (randomized or not) or retrospective clinical or medical-economic comparative studies having compared disposable scissors, trocars, and mechanical endoscopic staplers to the same instruments in reusable. Two different independent examiners extracted the relevant data. RESULTS: Among the 2882 articles found, 156 abstracts were retained for examination. After comprehensive analysis concerning the safety and effectiveness of the instruments, we included four articles. A study on trocars highlighted increased vascular complications with disposable instruments, and another study found more perioperative incidents with a hybrid stapler as opposed to a disposable stapler. As regards cost analysis, we included 11 studies, all of which showed significantly higher costs with disposable instruments. The results of the one study on carbon footprints showed that hybrid instruments leave four times less of a carbon footprint than disposable instruments. CONCLUSION: The literature on the theme remains extremely limited. Our review demonstrated that from a medical and economic standpoint, reusable medical instruments, particularly trocars, presented appreciable advantages. While there exist few data on the ecological impact, those that do exist are unmistakably favorable to reusable instruments.

Development and application of a protocol for extractables profiling from central venous catheters in neonates.

Peripherally inserted central catheters (PICC-lines) used in neonatology are made of thermoplastic polyurethane (TPU) or silicone. These materials usually contain substances that may leach into drug vehicles or blood. In this extractables study, we determined the optimal extraction conditions using TPU films containing defined amounts of butylhydroxytoluene (BHT) and then applied them on unused and explanted PICC-lines. Maceration and sonication tests were carried out with hexane, acetone and water as the extraction solvents. The analyses were performed using gas and liquid chromatography coupled with mass spectrometry detectors, as well as inductive coupled plasma optical emission spectroscopy to detect a wide range of extractables. We selected a limited list of substances to be sought from the usual adjuvants and monomers, related to their carcinogenic, mutagenic or reprotoxic properties and/or existence in endocrine disruptors lists. The TPU-film experiments showed that acetone was slightly better than hexane, and maceration better than sonication. When applied to PICC-lines, the extraction methods were almost similar but acetone was clearly better than hexane for TPU. From the 48 peaks initially observed in GC-MS, we ended up with 37 peaks to follow in TPU PICC-lines, among which were those of BHT and 4,4'-Methylenebis(cyclohexyl isocyanate) isomers. For silicone PICC-lines, out of 41 peaks initially observed in GC-MS, we followed 20 peaks, most of them being identified as cyclosiloxanes. Barium was the main inorganic element extracted for both PICC-lines. For TPU PICC-lines, the inter-batch variability was higher than for intra-batch, but in silicone devices both were similar. When compared to new PICC-lines, explanted TPU PICC-lines extracted peaks had a lower area under the curve (AUC), while the AUCs of the peaks were higher for the majority of silicone PICC-lines extract compounds. No identified substances were detected above their toxicological threshold, but isocyanates and cyclosiloxanes toxicity was mostly studied for other exposition routes than intravenous. The methods defined in this study were efficient in producing extractable profiles from both PICC-lines.

French multi-institutional cost-effectiveness analysis of gemcitabine plus nab-paclitaxel versus gemcitabine alone as second-line treatment in metastatic pancreatic cancer patients.

Context: In France, gemcitabine plus nab-paclitaxel (GEM-NAB) is heterogeneously used in metastatic pancreatic cancer due to disparities in its financial accessibility in the institutions. Objectives: GEM-NAB conduct a French multi-institutional cost-effectiveness analysis of GEM-NAB versus gemcitabine alone (GEM) as second-line treatment in pancreatic cancer patients. Design: All the unresected metastatic pancreatic ductal adenocarcinoma (PDAC) consecutive patients who received GEM-NAB (institution 1) or GEM alone (institutions 2 and 3) as second-line treatment after failure of a 5-fluorouracil based systemic chemotherapy regimen were screened. Methods: This study was conducted from the French national healthcare insurance perspective. The primary endpoint was the overall survival (OS) expressed in months, calculated from the date of the first second-line chemotherapy administration to death. Only direct (medical and non-medical) costs have been considered for this analysis. Data were collected retrospectively in one university hospital and two general hospitals. Results: The OS was significantly improved in patients receiving GEM-NAB (hazard ratio: 0.54, 95% confidence interval: 0.38-0.77, p = 0.001), with a median OS of 6.2 months (versus 4.1 months in patients receiving GEM alone). Taking into account the cost of GEM-NAB which was afforded by each institution, the incremental cost-effectiveness ratio was €1,449,231 by year of life (€40,256 per patient). In both groups, most of the costs were attributable to readmissions and outpatient chemotherapy administration. Conclusion: The issues of the article is based on the trade-off between the benefit in terms of OS of patients treated with GEM-NAB, which is minor (a gain of 2 months of survival, with an accumulated rate of grade ⩾ 3 non-hematological adverse effects) and the additional institutional cost (€25k per year of life for each patient treated). The debate is complex and refers to an ethical component, which is the cost of human life when no other therapeutic alternative is offered to the patient.

Fluorination of PVC medical devices to prevent plasticizers migration.

Medical devices (MD) are often made of plasticized polyvinylchloride (PVC). However, plasticizers may leach out into infused solutions and expose the patients to a toxic risk. The aim of the present work is to fluorinate plasticized PVC tubular MDs to create a barrier layer on their internal surface, and to study the impact of such a chemical treatment on the migration of the plasticizers. Following fluorination by pure molecular fluorine, the physico-chemical characterization of these modified MDs was carried out using various spectroscopic and microscopic techniques or tensile tests, evidencing the formation of covalent C-F bonds on the surface of the treated samples without modification of their mechanical and optical properties. The migration of plasticizers from fluorinated MDs was assessed using gas chromatography coupled with mass spectrometry and was found considerably decreased in comparison with the pristine MDs. After 24 h, the amount of tri-octyltrimellitate plasticizer (TOTM) detected in migrates from fluorinated MDs was even lower than the limit of quantification. Complementary cytotoxicity assays were performed according to the ISO EN 10993-5 standard, showing that the new fluorinated material does not cause a cytotoxic effect on L929 cells.

Development and Stability of a New Formulation of Pentobarbital Suppositories for Paediatric Procedural Sedation.

Pentobarbital is a drug of choice to limit motion in children during paediatric procedural sedations (PPSs). However, despite the rectal route being preferred for infants and children, no pentobarbital suppositories are marketed, and therefore they must be prepared by compounding pharmacies. In this study, two suppository formulations of 30, 40, 50, and 60 mg of pentobarbital sodium were developed using hard-fat Witepsol® W25 either alone (formulation F1) or with oleic acid (formulation F2). The two formulations were subjected to the following tests described in the European Pharmacopoeia: uniformity of dosage units, softening time, resistance to rupture, and disintegration time. The stability of both formulations was also investigated for 41 weeks of storage at 5 ± 3 °C using a stability-indicating liquid chromatography method to quantify pentobarbital sodium and research breakdown product (BP). Although both formulae were compliant to uniformity of dosage, the results were in favour of a faster disintegration of F2 compared to F1 (-63%). On the other hand, F1 was found to be stable after 41 weeks of storage unlike F2 for which several new peaks were detected during the chromatographic analysis, suggesting a shorter stability of only 28 weeks. Both formulae still need to be clinically investigated to confirm their safety and efficiency for PPS.

Regulatory assessment of nano-enabled health products in public health interest. Position of the scientific advisory board of the French National Agency for the Safety of Medicines and Health Products.

Nanomaterials are present in a wide variety of health products, drugs and medical devices and their use is constantly increasing, varying in terms of diversity and quantity. The topic is vast because it covers nanodrugs, but also excipients (that includes varying proportions of NMs) and medical devices (with intended or not-intended (by-products of wear) nanoparticles). Although researchers in the field of nanomedicines in clinical research and industry push for clearer definitions and relevant regulations, the endeavor is challenging due to the enormous diversity of NMs in use and their specific properties. In addition, regulatory hurdles and discrepancies are often cited as obstacles to the clinical development of these innovative products. The scientific council of the Agence Nationale de Sécurité du Médicament et des produits de santé (ANSM) undertook a multidisciplinary analysis encompassing fundamental, environmental and societal dimensions with the aim of identifying topics of interest for regulatory assessment and surveillance. This analysis allowed for proposing some recommendations for approximation and harmonization of international regulatory practices for the assessment of the risk/benefit balance of these products, considering as well the public expectations as regards efficacy and safety of nanomaterials used in Health products, in terms of human and environmental health.

Guidelines for reducing the environmental impact of general anaesthesia.

OBJECTIVE: To provide guidelines for reducing the environmental impact of general anaesthesia. DESIGN: A committee of ten experts from SFAR and SF2H and SFPC learned societies was set up. A policy of declaration of competing interests was applied and observed throughout the guideline-writing process. Likewise, it did not benefit from any funding from a company marketing a health product (drug or medical device). The committee followed the GRADE® method (Grading of Recommendations Assessment, Development and Evaluation) to assess the quality of the evidence on which the recommendations were based. METHODS: We aimed to formulate recommendations according to the GRADE® methodology for three different fields: anaesthesia vapours and gases; intravenous drugs; medical devices and the working environment. Each question was formulated according to the PICO format (Population, Intervention, Comparator, Outcome). The literature review and recommendations were formulated according to the GRADE® methodology. RESULTS: The experts' work on the synthesis and application of the GRADE® method led to the formulation of 17 recommendations. Since the GRADE® method could not be entirely applied to all of the questions, some of the recommendations were formulated as expert opinions. CONCLUSION: Based on strong agreement between experts, we produced 17 recommendations designed to guide reducing the environmental impact of general anaesthesia.

Medical devices used in NICU: The main source of plasticisers' exposure of newborns.

Phthalates and other plasticisers are extensively used in medical devices (MD) from which they can leach out and lead to potential multiple problems for the patients. This exposure is a major issue because it is associated with reproductive and neurodevelopment disorders. The Neonatal Intensive Care Units (NICU) population is at high risk due to the daily intensive medical interventions, the reduced ability of newborns to remove these contaminants and their higher sensitivity to endocrine disruptors. We conducted a multicentric biomonitoring study to assess and compare the urinary levels of DEHP (di-(2-ethylhexyl)phthalate), DEHTP (di-(2-ethylhexyl)terephthalate) and TEHTM (tri-(2-ethylhexyl)trimellitate) metabolites as biomarkers of this exposure during and after the newborns' stay in NICU. Daily urinary samples were collected in NICU and at discharge from the hospital for each patient. MD sources and exposure factors were also investigated. 508 urinary samples from 97 patients enrolled in centres 1 and 2 (C1/C2) were collected. The exposure of newborns to DEHP was greater than that of DEHTP and TEHTM, with a median concentration of DEHP metabolites (C1:195.63 ng/mL;C2:450.87 ng/mL) respectively 5 to 10 times higher and 57 to 228 times higher than the median concentrations of DEHTP and TEHTM metabolites. The urinary concentrations of DEHP and TEHTM metabolites were significantly lower at discharge than in NICU, with a 18-and 35-fold decrease for DEHP and a 4 and 8-fold decrease for TEHTM, respectively for C1 and C2, but were similar for DEHTP metabolites. MD used for respiratory assistance, infusion therapy,enteral nutrition and transfusion were the main sources of exposure. Smaller gestational age and body weight significantly increased the newborns' exposure. The elevated levels of DEHP metabolites in NICU patients are still alarming. Additional efforts are necessary to promote its substitution in MD by possibly safer alternatives such as TEHTM and DEHTP, particularly when used for the care of newborns.

Evaluation of color changes during stability studies using spectrophotometric chromaticity measurements versus visual examination.

Stability studies are essential to be able to assign an expiration date to medications. Color variation is one of the organoleptic characteristics of actives substances or medications which can indicate the presence of contaminations, impurities or degradations products. However there is no data available comparing the often used visual examination with spectrophotometric measurements during stability studies. The aim of this study was therefore to evaluate precisely how different the two methods are, by comparing the change of color of two drug formulations chosen as models, assessed by visual examination versus a spectrophotometric colorimetric analysis. Paracetamol and parenteral nutrition solutions were stored in stress conditions for up to 46 days, and were subjected to a visual examination using color reference solutions and to lightness and chromaticity measurement to determine their specific color by UV-Vis spectrophotometry. The color of paracetamol solutions changed faster when exposed to stress condition (light), as did the PNS when exposed to heat. In both cases, color variations were detected earlier and more precisely by UV-Vis spectrophotometry than by visual examination. Color measurement using an UV-Vis spectrophotometry should advantageously replace visual examination when assessing colors changes during drug stability studies.

Insulin Adsorption onto PE and PVC Tubings.

We investigate the adsorption of insulin onto PE and PVC materials by using HPLC measurements and computer simulations. We interpret the experiments by calculating the Gibbs free energy profiles during the adsorption process. The values of free energy of adsorption show a good agreement with the experimental measurements. The adsorption of insulin onto the different materials is characterized through the conformational changes with respect to its conformation in water and the interfacial regions, which are described by specific arrangements of polymer chains, water, insulin, and plasticizer molecules.

Ex Vivo Model to Assess the Exposure of Patients to Plasticizers from Medical Devices during Pre-CAR-T Cells' Apheresis.

BACKGROUND: The treatment of relapsed or refractory leukemia remains a major problem. Among the new therapeutic approaches, the use of modified T lymphocytes, called chimeric antigen receptor T cells (CAR-T cells), seems promising. The first step of their preparation is leukapheresis, which involves the collection of mononuclear cells from the patient. This medical procedure requires numerous medical devices (MDs) made of plasticized polyvinylchloride (PVC). These compounds can leach out of the devices during contact with the patient's blood. The aim of our study was to evaluate the migration of the plasticizers contained in the MD during a simulated pre-CAR-T cell leukapheresis procedure, and to measure the patient's and their lymphocytes' exposure to them. METHODS: The qualitative and quantitative composition of the MD used for pre-CAR-T cell apheresis was determined by gas chromatography-mass spectrometry (GC-MS). Then, an ex vivo leukapheresis model using an ethanol/water simulant was performed to evaluate the plasticizers' migration under simulated clinical conditions of pre-CAR-T cells' cytapheresis. The plasticizers released into the simulant were quantified by GC-MS. RESULTS: Diethylhexylphthalate (DEHP) was found in the apheresis kit, with amounts ranging from 25% to 59% (g/100 g of PVC). Bis(2-ethylhexyl) adipate was detected at trace levels. A total of 98.90 ± 11.42 mg of DEHP was released into the simulant, corresponding to an exposure dose of 1.4 mg/kg for a 70 kg patient. CONCLUSIONS: Patients undergoing a pre-CAR-T cell apheresis are mainly exposed to DEHP, which can impact their health because of its endocrine disruption effect, but could also lead to a decrease in CAR-T cells' efficiency/quality.