Surface properties and bacterial adhesion on polyurethane central catheters: Impact of ethanol lock solution.

It was shown in the literature that ethanol locks have a positive effect on preventing catheter-related infections in patients with central venous catheters without causing any microbial resistance. However, ethanol is known to interact with polyurethanes. The consequences of this interaction on the catheter surface properties were studied as it can impact the biocompatibility of the material and the adhesion phenomena onto the surface. No physical and chemical degradation was put into evidence, but low molecular weight compounds such as additives were extracted from the catheter bulk or migrated and exudated onto its surface. Nevertheless, as far as bacterial adhesion is concerned, after the catheter was locked and the lock removed, the surface modifications promoted no adhesion.

Impact of mechanical stress on flexible tubing used for biomedical applications: Characterization of the damages and impact on the patient's health.

Flexible tubing is a key part of a lot of medical devices used in hospital, but may be subjected to a lot of various mechanical stresses that can led to the failure or to complications for the patients. The nature and causes of these mechanical stresses were listed for peristaltic pump tubing, infusion set tubing and catheters. Their consequences in term of tubing damages and particular contamination were reported. The impact of the chemical nature of the tubing, of its size and also the impact of various parameters of the clinical acts were reviewed. Last the consequences for the patient's health were discussed.

Investigating the static or dynamic flexural and compressive stresses on flexible tubing: Comparison of clamp and peristaltic pump impact on surface damages and particles leaching during infusion acts.

This paper deals with the impact of the mechanical stresses on plasticized PVC infusion tubing. Stresses due to clamping were compared to those due to the use of a peristaltic pump. The degradation of the inner surface of plastic tubing due to a dynamic load with repeated flexion and compression was extensively studied in the case of peristaltic pump stress during extracorporeal (EC) acts. Even if clamping results in a less repeated stress, we show it can also lead to damages on the inner lumen of the tubing, especially in static conditions. As these degradations were responsible of particle shedding in the case of EC processes, a first evaluation of particular contamination was performed on the stressed infusion tubes.

Effects of electron beam sterilization on polyethylene terephthalate: Physico-chemical modifications and formation of non-volatile organic extractables.

Our investigations hereby involve the effects of ionizing radiation as a sterilization method, and especially electron beams, on a medical grade Polyethylene Terephthalate (PET). Ionizing radiations are known to induce free radicals formation in the polymer that will then either degrade or crosslink, depending on its chemical nature, ionizing type and irradiation atmosphere (Charlesby, 1967; Dole, 1972 and Dole, 1973). The evaluation of packaging material modifications under radiation sterilization is of great interest and the objective of our paper is to focus on both PET volume modifications and extractable analyses after electron beam sterilization. As regards the polymeric matrix and after sterilization, we did not observe by means of spectral analyses, any single chemical modification whatsoever, whereas by thermal techniques we evidenced polymer chain scissions. As for the non-volatile organic extractables, we further substantiate the presence of numerous compounds, namely oligomers and trimers especially, along with benzoic and terephthalic acids in particular. With respect to pharmaceutical stakes however, we claim herein that the 25kGy sterilization dose used, triggers oligomers and extractables formation, a result which is promising for further risk analysis.

Imatinib: Major photocatalytic degradation pathways in aqueous media and the relative toxicity of its transformation products.

Imatinib (IMA) is a highly potent tyrosine kinase inhibitor used as first-line anti-cancer drug in the treatment of chronic myeloid leukemia. Due to its universal mechanism of action, IMA also has endocrine and mutagenic disrupting effects in vivo and in vitro, which raises the question of its environmental impact. However, to date, very little information is available on its environmental fate and the potential role of its transformation products (TPs) on aquatic organisms. Given the IMA resistance to hydrolysis and direct photolysis according to the literature, we sought to generate TPs through oxidative and radical conditions using the AOPs pathway. Thus, the reactivity of the cytotoxic drug IMA in water in the presence of OH and h+ was investigated for the first time in the present work. In this regard, a non-targeted screening approach was applied in order to reveal its potential TPs. The tentative structural elucidation of the detected TPs was performed by LC-HRMSn. The proposed approach allowed detecting a total of twelve TPs, among which eleven are being described for the first time in this work. Although the structures of these TPs could not be positively confirmed due to lack of standards, their chemical formulas and product ions can be added to databases, which will allow their screening in future monitoring studies. Using the quantitative structure-activity relationship (QSAR) approach and rule-based software, we have shown that the detected TPs possess, like their parent molecule, comparable acute toxicity as well as mutagenic and estrogenic potential. In addition to the in silico studies, we also found that the samples obtained at different exposure times to oxidative conditions, including those where IMA is no longer detected, retained toxicity in vitro. Such results suggest further studies are needed to increase our knowledge of the impact of imatinib on the environment.

Characterization of the surface physico-chemistry of plasticized PVC used in blood bag and infusion tubing.

Commercial infusion tubing and blood storage devices (tubing, blood and platelets bags) made of plasticized PVC were analyzed by spectroscopic, chromatographic and microscopic techniques in order to identify and quantify the additives added to the polymer (lubricants, thermal stabilizers, plasticizers) and to put into evidence their blooming onto the surface of the devices. For all the samples, deposits were observed on the surface but with different kinds of morphologies. Ethylene bis amide lubricant and metallic stearate stabilizers were implicated in the formation of these layers. In contact with aqueous media, these insoluble deposits were damaged, suggesting a possible particulate contamination of the infused solutions.

Studying DEHP migration in plasticized PVC used for blood bags by coupling Raman confocal microscopy to UV spectroscopy.

Plasticized PVC is widely used to make medical devices such as tubing, perfusion bags and blood bags. By using confocal Raman microscopy on a PVC sheet plasticized with around 40% of di-(2-ethylhexyl)phthalate (DEHP), we propose a simple and sensitive approach to studying and understanding the diffusion of plasticizers from polymers into the surrounding media. Moreover, we sought to correlate our findings to standard measurements conducted by UV spectroscopy. This study showed differences in the concentration gradient observed due to the diffusion of the plasticizer inside a PVC sheet. We can thus follow the critical DEHP ratios that can impact the diffusion process. Water and ethanol were chosen as storage media: in ethanol, the lowest concentration of DEHP was observed at the surface resulting in the formation of a less plasticized layer near the interface; unlike ethanol, PVC sheets stored in water showed a greater concentration of DEHP on the film surface as an exudation of DEHP onto the surface.

Impact of the nature and concentration of plasticizers on the ability of PVC to sorb drug.

The sorption of a drug by an infusion set may dramatically reduce the drug delivery efficiency. In this paper, we investigated how the drug sorption, in static conditions, is affected by the plasticizer's nature and ratio in the case of plasticized PVC, one of the most common material for infusion set tubing. Within the study, the drug concentration in diazepam solutions was studied after contact with PVC films containing different amounts of DEHP, DEHT, TOTM and DINCH® plasticizers. Moreover the partition coefficients between material and water were calculated. The drug sorption levels were equivalent for the different plasticizers and there was a plasticizer ratio for which the drug uptake was enhanced. As a consequence, the amount of sorbed drug might not be only linked to the amount of plasticizer in the film and to the solubility of the drug in the plasticizer alone: it must probably depend on specific interactions between plasticizer and PVC.

Embolization biomaterial reinforced with nanotechnology for an in-situ release of anti-angiogenic agent in the treatment of hyper-vascularized tumors and arteriovenous malformations.

A polymer based material was developed to act as an embolic agent and drug reservoir for the treatment of arteriovenous malformations (AVM) and hyper vascularized solid tumors. The aim was to combine the blocking of blood supply to the target region and the inhibition of the embolization-stimulated angiogenesis. The material is composed of an ethanolic solution of a linear acrylate based copolymer and acrylate calibrated microparticles containing nanospheres loaded with sunitinib, an anti-angiogenic agent. The precipitation of the linear copolymer in aqueous environment after injection through microcatheter results in the formation of an in-situ embolization gel whereas the microparticles serve to increase the cohesive properties of the embolization agent and to form a reservoir from which the sunitinib-loaded nanospheres are released post-embolization. The swollen state of the microparticles in contact with aqueous medium results in the release of the nanospheres out of microparticles macromolecular structure. After the synthesis, the formulation and the characterization of the different components of the material, anti-angiogenic activity was evaluated in vitro using endothelial cells and in vivo using corneal neovascularization model in rabbit. The efficiency of the arterial embolization was tested in vivo in a sheep model. Results proved the feasibility of this new system for vascular embolization in association with an in situ delivery of anti-angiogenic drug. This combination is a promising strategy for the management of arteriovenous malformations and solid tumors.

Resonance enhanced AFM-IR: a new powerful way to characterize blooming on polymers used in medical devices.

In this paper we demonstrated the application of resonance enhanced AFM-IR to the study of the medical device surfaces. Surface state is one of the most important parameter on the biocompatibility of an implantable medical device. By using this new technique, it was possible to obtain with high resolution topographic and chemical maps and to identify the chemical nature of very thin deposit observed on the surface. This was illustrated with the case of lubricant exudation on polyurethane used in the making of implantable catheters.

Blooming of Irganox 3114® antioxidant onto a medical grade elastomer. Impact of the recrystallization conditions on the antioxidant polymorphism, on the film wettability and on the antioxidant leachability.

Studying the blooming and recrystallization of additives onto the surface of polymer medical devices is of a great interest because it can affect the biocompatibility of the material. The polymorphism of a phenolic antioxidant (Irganox 3114(®)) used as an additive in medical devices and pharmaceutical packaging was studied: two different polymorphs were characterized by differential scanning measurements, FTIR and X-ray diffraction analyses. Then, the behavior of the additive in medical grade polyurethane films was described: a recrystallization into the stable polymorphic form was observed onto the polymer surface after annealing at different temperatures. The morphology observed depends not only on the additive/polymer ratio but also on the whole amount of additive in the polymer film. Depending on the recrystallization morphology, the wettability with water could be lowered and the leachability of the additives into aqueous media could be favored.

Evaluation of trace elements released by edible clays in physicochemically simulated physiological media.

Physicochemical simulation (pH, electrolytes and temperature) of three physiological media was carried out in order to follow the release of trace elements contained in seven edible clays (mainly kaolinite, illite, muscovite and quartz) collected from the West African countries of Côte d'Ivoire, Guinée and Sénégal. These clays are ingested by pregnant women for diverse reasons that are related to their condition. Simulated oral (6.5

Role of ceramide structure and its microenvironment on the conformational order of model stratum corneum lipids mixtures: an approach by FTIR spectroscopy.

The aim of this study is to investigate the influence of ceramide head group architecture and free fatty acid (another main class of stratum corneum lipids) or protein (keratin), on the lamellar organization of the ceramide auto-associated in model films mimicking lipid organization within the stratum corneum. FTIR spectroscopy is a powerful technique for investigating the structure of such systems. This technique has already been used to characterize phase transitions of the SC and of related model systems. As temperature is known to modify the conformational order of lipids, we used it as a variable parameter to monitor the differences in the conformational stability of ceramides. Our study included four ceramides: ceramide 2, 3, 5 and 6 which differ by their head group architecture. Two kinds of lipid-lipid interactions were studied: non-polar and polar. We noted some structural factors which participated to the organizational behavior: insaturation of alkyl chain, alpha-hydroxyl on fatty acid moiety and sphingosine or phytosphingosine head group. There is a direct interaction of palmitic acid on alkyl chains organization and a weak interaction with polar head group in presence of keratin, both provoking a destabilization of the ceramidic orthorhombic organization.

ATR-FTIR spectroscopy: a chemometric approach for studying the lipid organisation of the stratum corneum.

The barrier function of skin resides in the lipid components of the stratum corneum, particularly their spatial organisation. FTIR spectroscopy has already been used as a relevant tool to study this lipid organisation: IR vibration band shifts have been attributed to the variations in lipid organisation induced by temperature. Our study included a stratum corneum model, composed of the three main lipids: palmitic acid as an example of fatty acids, cholesterol and ceramide III as an example of ceramide. Different films with various ratios of these lipids were studied. In our analytical strategy, the interest of using a chemometric analysis of global data obtained from ATR-FTIR spectra to highlight the main interactions involved in the molecular organisation of lipids has been demonstrated. Two kinds of interaction between the three main lipids have been shown: a non polar interaction between the long hydrocarbon chains and a polar interaction as the hydrogen bonding between polar functional groups. By varying the lipid ratio, we have shown first that the relative importance of each interaction was modified, second, that the induced modification of organisation can be detected by chemometric analysis of the ATR-FTIR spectra. The role of each kind of lipid in the organisation has been discussed. In conclusion, associating the ATR-FTIR with chemometric treatment is a promising tool: firstly, to understand the consequence of lipid relative compositions on the structural organisation of the stratum corneum, secondly, to show the relationship between lipid organisation and percutaneous penetration data. Indeed, this methodology will be transposed to in vivo studies with IR measurements through a probe.

Water state characterization, swelling behavior, thermal and mechanical properties of chitosan based networks.

Two kinds of chitosan-based hydrogels, a crosslinked chitosan reference gel and a chitosan-poly(ethylene oxide) semi-interpenetrating network (semi-IPN), with potential pH-sensitive swelling and drug delivery properties are characterized. Swelling studies were performed on the two kinds of hydrogels by differential scanning calorimetry (DSC) at pH 1.2 and by the gravimetric method at pH 1.2 and pH 7.2. Both methods lead to similar results. If pH-dependent swelling properties were observed with both hydrogels, they were however improved for the semi-IPN. The amount of bound water in the xerogels could be determined from DSC measurements and a thermogravimetric analysis. The results obtained by both techniques were in good agreement and indicated that the semi-IPN contained more bound water than the reference gel probably due to the presence of the hydrophilic poly(ethylene oxide) chains. Young modulus of the swollen hydrogels was determined by indentation analysis. The semi-IPN displayed improved mechanical properties compared to the reference gel.

Safety and quality of food contact materials. Part 1: evaluation of analytical strategies to introduce migration testing into good manufacturing practice.

The results of a research project (EU AIR Research Programme CT94-1025) aimed to introduce control of migration into good manufacturing practice and into enforcement work are reported. Representative polymer classes were defined on the basis of chemical structure, technological function, migration behaviour and market share. These classes were characterized by analytical methods. Analytical techniques were investigated for identification of potential migrants. High-temperature gas chromatography was shown to be a powerful method and 1H-magnetic resonance provided a convenient fingerprint of plastic materials. Volatile compounds were characterized by headspace techniques, where it was shown to be essential to differentiate volatile compounds desorbed from those generated during the thermal desorption itself. For metal trace analysis, microwave mineralization followed by atomic absorption was employed. These different techniques were introduced into a systematic testing scheme that is envisaged as being suitable both for industrial control and for enforcement laboratories. Guidelines will be proposed in the second part of this paper.

Plasma-based sterilization: effect on surface and bulk properties and hydrolytic stability of reprocessed polyurethane electrophysiology catheters.

Plasma-based sterilization is a promising alternative to ethylene oxide (EO) for reprocessing of electrophysiology catheters. To assess its safety in terms of material damage, modifications of surface and bulk properties as well as hydrolytic stability of sterilized catheters were evaluated. Polyurethane (PU) single-use electrophysiology catheters were subjected to one, five, and ten sterilization cycles by Sterrad-100S and Plazlyte, as well as by pure EO for comparison. Surface analysis techniques (ATR-FTIR, XPS, DCA) showed oxidation limited to the near-surface layer induced by both plasma-based sterilizers, whereas EO induced slight but deeper alkylation. Using bulk analysis techniques (RP-HPLC, SEC), oligomer alteration was observed after all three sterilization techniques, without modification of molecular weights. Hydrolytic stability of catheters was slightly changed by plasma-based sterilization, with a small increase in released oligomers. Finally, although Plazlyte and Sterrad are both plasma-based techniques, they induced different impacts on catheters, such as the degradation of an additive with Sterrad, and a clear difference in coloration with Plazlyte.

[Mycobacterium avium complex infections: the point on the treatments]. / Infections à mycobactéries du complexe aviaire: le point sur les traitements.

Mycobacterium avium complex (MAC) infections are the most frequent opportunistic infections in AIDS. Since progress in antiretroviral drugs enables AIDS patients to survive longer, these infections involve an increasing number of sick people. Few controlled assays have evaluated the efficiency of several antibiotics. When used in monotherapy, clarithromycin (one gram twice a day) appeared as the most efficient drug while the effectiveness of azithromycin, clofazimine, rifampin and liposomal encapsulated gentamicin have not been truly proved. Due to its bacteriologic and clinical effects, the most interesting polytherapeutic scheme is the association of clarithromycin (1 g twice a day), ethambutol (15 mg per kg and per day) and rifabutin (600 mg per day).

[Orphan drugs: problem of public health and economic stakes]. / Les médicaments orphelins: problème de santé publique et enjeux économiques.

Orphan drugs (OD) qualify as drugs scientifically viable but not viable from an economic point of view either because the number of patients who might benefit is too small or because the populations concerned are too poor to afford the drugs. Sick people who could be treated by OD and their families have been fighting for years to induce authorities in charge of health to set up a programme to stimulate research into new treatment for rare diseases. The United States, initiated work in order to confer status on OD leading to the Orphan Drug Act in 1983. It defined the conditions for attribution of the OD status and also made attractive proposals to pharmaceutic industries in order to improve their development. More recently, in 1993, Japan took similar decisions, while the European Union and France are also on the way, as recent meetings of European ministers of health show. In contrast, developing countries are still excluded from medical research as very few tropical diseases have treatment. Legislation for OD, first planned to make up for the high costs of research and development, proved its efficiency. But ODs must move to a new status as some are now becoming the object of important economic stakes.

[Characterization and simultaneous assay of polymers and additives composing multilayer plastic material for pharmaceutical use by FTIR]. / Caractérisation et dosage simultanés des polymères et des additifs constitutifs d'un matériau plastique multicouches à usage pharmaceutique, par IRFT.

Multilayer plastic materials provide useful solutions for primary pharmaceutical formulae (maintaining physical properties, compatibility with contents, protection against exterior agents). Fourier transform infrared spectometry is an ideal method to identify and quantify the different polymers and additives. Each functional group has a characteristic band which can be selected and rapidly identified for routine quality control. The proportional quantities of each polymers in the multilayer system can be determined directly using the characteristic bands for each functional group. The technique was applied to the analysis of heat-formed platelets made of polyvinyl chloride and polyvinylidene chloride.