Analysis of plasticizers in PVC medical devices: Performance comparison of eight analytical methods.

A wide variety of medical devices (MDs) used in hospitals are made of flexible plasticized polyvinylchloride (PVC). Different plasticizers are present in variable amounts in the PVC matrix of the devices and can leach out into the infused solutions and may enter into contact with the patients. The ARMED1 project aims to assess the migration of these plasticizers from medical devices and therefore the level of exposure in patients. For the first task of the project, eight methods were developed to directly detect and quantify the plasticizers in the PVC matrix of the MDs. We compared the overall performances of the analytical methods using standardized and validated criteria in order to provide the scientific community with the guidance and the technical specifications of each method for the intended application. We have shown that routine rapid screening could be performed directly on the MDs using the FTIR technique, with cost-effective analyses. LC techniques may also be used, but with limits and only with individual quantification of the main plasticizers expected in the PVC matrix. GC techniques, especially GC-MS, are both more specific and more sensitive than other techniques. NMR is a robust and specific technique to precisely discriminate all plasticizers in a MD but is limited by its cost and its low ability to detect and quantify plasticizer contamination, e.g. by DEHP. All these results have been confirmed by a real test, called the " blind test " carried out on 10 MD samples.

The consequences of physical post-treatments (microwave and electron-beam) on food/packaging interactions: A physicochemical and toxicological approach.

The safety of microwave and electron-beam treatments has been demonstrated, in regards to the formation of reaction products that could endanger human health. An integrated approach was used combining the potential toxicity of all the substances likely to migrate to their chemical characterizations. This approach was applied to polypropylene (PP) films prepared with a selection of additives. Components were identified by liquid and gas chromatography using a mass selective detector system. Their potential toxicity was assessed using three in vitro short-term bioassays and their migrations were carried out using a standards-based approach. After the electron-beam treatment some additives decomposed and there was a significant increase in the polyolefin oligomeric saturated hydrocarbons concentration. PP prepared with Irgafos 168 led to a significantly strong cytotoxic effect and PP prepared with Irganox 1076 induced a dose-dependant estrogenic effect in vitro. Migration values were low and below the detection limit of the analytical method applied.

Migration of plasticizers from PVC medical devices: Development of an infusion model.

Alternatives to DEHP plasticizers are used in various PVC medical devices (MD) for infusion. As they are able to migrate from these MDs into infused solutions, they may come into contact with patient. Different and specific clinical parameters influence their migration in at-risk situations such as infusion. In contrast to the regulations for Food Contact Materials (MCDA), there is currently no acceptable migration limits for the use of these plasticizers in clinical situations. In order to assess their migration, and thus control the risks linked to these MDs, we developed a migration model for the plasticizers in MDs. To this end, we applied a cross-disciplinary methodological process similar to that used in the food-processing industry, taking into account the MDs' conditions of use in clinical practice. The simulation model is simple and includes the following conditions: MD should be tested with a dynamic method that respects our established clinical assumption (2 L of infused solutions via 13 dm(2) of plasticized PVC), at a temperature of 25 °C and during 24 h of contact, using a 50/50 (v/v) ethanol/water simulant. This model could be proposed as a tool for the safety evaluation of the patients' exposure risk to plasticizers from PVC medical devices for infusions.

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.

Fortum stability in different disposable infusion devices by pyridine assay.

The stability of ceftazidime in 5% dextrose injection and 0.9% sodium chloride injection when stored in a different disposable infusion device was determined. Solutions of ceftazidime 40 mg/ml were used to fill the drug administration devices. Stability was determined for both 5% dextrose injection and 0.9% sodium chloride injection solutions at 37 degrees C in four disposable infusion devices. Ceftazidime and its mean degradation product, pyridine, were simultaneously assayed in triplicate by a stability-indicating high-performance liquid chromatographic (HPLC) method. This method was simple, sensitive (limit of quantitation (LOQ), 2 ng injected for both compounds), rapid (run time was 7 min) and precise (mean recovery was 100.5+/-2.9 and 103.6+/-1.9% for pyridine and ceftazidime, respectively). The ceftazidime stability in the 5% dextrose solution was lower than in the 0.9% sodium chloride solution. When stored at 37 degrees C in a disposable infusion device, the stability of the ceftazidime is included in large hourly range, depending strongly on the manufacturer. The stability of ceftazidime exceed 19 h in none studied cases. The pyridine formed in 24 h was in the range of 100-400 mg depending on devices and infusions.

Cardiac anticholinergic effects of procainamide and its N-acetylated metabolite: experimental pharmacological and radioligand binding studies.

1. The cardiac anticholinergic effects of procainamide (1 mg kg(-1) min(-1)) and its N-acetylated metabolite (NAPA) at equimolar dose (1.16 mg kg(-1) min(-1)) were studied using in vivo experimental pharmacological and in vitro radioligand binding studies. 2. Procainamide and NAPA progressively reduced vagal stimulation-induced bradycardia in chloralose-anaesthetized dogs. As indicated by the ED50, the vagolytic activity of NAPA is 1.5-2.0 times weaker than that of procainamide. Both drugs increased heart rate, with lowering of mean blood pressure during the second part of procainamide infusion, but not during NAPA infusion. 3. Binding studies on rat heart membranes yielded Ki values that were 1.5 times higher for NAPA than for procainamide. 4. These results show that NAPA exerts a weaker cardiac vagolytic action than procainamide, which is probably linked to a lower ability to bind to cardiac muscarinic receptors.

Contribution of vagal blockade to the tachycardia induced by the antimuscarinic agents atropine and pirenzepine.

1. The cardiac cholinergic blockade and the chronotropic effect of the widely differing antimuscarinic drugs atropine and pirenzepine were investigated in the dog. 2. In conscious dogs, suppression of the parasympathetic system with atropine (0.2 mg kg-1 h-1) causes marked brief cardioacceleration (234 +/- 13 beats min-1) while pirenzepine (3 mg kg-1 h-1) causes moderate but persistent cardioacceleration (179 +/- 13 beats min-1). After suppression of the influence of the cardiac sympathetic system these cardioaccelerator effects are attenuated, particularly those of pirenzepine. 3. The effects of vagal stimulation are blocked completely and persistently by both agents. 4. When the cardioinhibitory action of the vagus nerve is blocked by pirenzepine the induced tachycardia can be increased by atropine, which causes an additional cardioacceleration (25 +/- 9 beats min-1). 5. These results show that the tachycardia induced by antimuscarinic agents is not only due to vagal blockade. The different mechanisms which may be involved are discussed. The results suggest that pirenzepine can suppress cholinergic influence on the heart more electively than atropine, which induced an 'excess tachycardia'. Also, intrinsic heart rate can be approached more closely when pirenzepine is used to suppress the parasympathetic system, than with atropine.