T. Dine

Exposure of hemodialysis patients to di-2-ethylhexyl phthalate

The migration of di-2-ethylhexyl phthalate (DEHP) from dialyzers was studied in 21 patients with chronic renal failure undergoing maintenance hemodialysis. The circulating concentrations of DEHP were measured by high performance liquid chromatography in blood of patients obtained from the inlet and the outlet of the dialyzer during a 4-h dialysis session. During treatment of renal failure using plasticized tubing, the plasma level of DEHP increased. On average, an estimated 75.2 mg of DEHP was extracted from the dialyzer during a single dialysis session, with a range of 44.3-197. 1 mg. On the other hand, the total amount of DEHP retained by the patient during the dialysis session was evaluated by the difference between the AUCout and the AUCin and ranged from 3.6 to 59.6 mg. The rate of extraction of DEHP from the dialyzer was correlated (r=0.705, P<0.05) with serum lipid content (cholesterol and triglyceride).So, we confirmed that patients on hemodialysis are always regularly exposed to considerable amounts of DEHP. However, several metabolic effects have been reported in various animal species following treatment with DEHP, such as changes in lipid metabolism and in hepatic microsomal drug-metabolizing enzyme activities. DEHP is now a well-known hepatic peroxisomal proliferator in rodents and an inducer of many peroxisomal and non-peroxisomal enzymes. So, lipid metabolism modifications and hepatic changes observed in hemodialysis patients could be explained from chronic exposition to DEHP. In the coming years, it seems necessary to reconsider the use of DEHP as a plasticizer in medical devices. Highly unacceptable amounts of DEHP leached during the dialysis session could be easily avoided by careful selection of hemodialysis tubing.

Comparative study of the leachability of di(2-ethylhexyl) phthalate and tri(2-ethylhexyl) trimellitate from haemodialysis tubing.

The leachability of both Di(2-ethylhexyl) phthalate (DEHP) and Tri(2-ethylhexyl) trimellitate (TEHTM) or Trioctyl trimellitate (TOTM) from haemodialysis tubing was investigated in 20 patients with chronic renal failure undergoing maintenance haemodialysis. The blood tubing made of common polyvinyl chloride (PVC) plasticized with DEHP (group 1 patients) were replaced with tubing plasticized with TOTM-DEHP (group 2 patients). The patient blood obtained from the inlet and the outlet of the dialyzer was analyzed during a 4 h-dialysis session. Thus, the circulating concentrations of both DEHP and TOTM resulting from the release from dialyzer tubes were estimated using High-performance Liquid chromatograph (HPLC). With the common PVC-DEHP blood tubing, a DEHP quantity of 122.95+/-33.94 mg was extracted from tubing during a single dialysis session (ranging from 55 to 166.21 mg). During the same period, the total amounts of DEHP retained by the patients were 27.30+/-9.22 mg (ranging from 12.50 to 42.72 mg). As for blood tubing plasticized with TOTM-DEHP, 41.80+/-4.47 mg of DEHP and 75.11+/-25.72 mg of TOTM were extracted. During the same period, the amounts of DEHP and TOTM retained by the patients were 3.42+/-1.37 mg and 4.87+/-2.60 mg, respectively. The extraction rate both plasticizers was correlated with serum lipid content (cholesterol+triglyceride) (r(2)=0.75 for DEHP and r(2)=0.64 for TOTM). In the present investigation, less TOTM and DEHP were apparently released from haemodialysis tubing plasticized with TOTM-DEHP than DEHP released from haemodialysis tubing plasticized with DEHP only. TOTM seems to be a superior alternative to DEHP for use in medical devices because of its potential lower leachability. To recommend it as an alternative plasticizer, its possible toxicity towards human body should be investigated before it can be used routinely. However, patients undergoing haemodialysis using tubing plasticized with DEHP only are regularly exposed to non negligible amounts of DEHP. In view of several biological effects previously reported, it is time to reconsider the use of DEHP only as a plasticizer.

Evaluation of childhood exposure to di(2-ethylhexyl) phthalate from perfusion kits during long-term parenteral nutrition.

Leachability of the plasticizer di(2-ethylhexyl) phthalate (DEHP) from administration sets into intravenous parenteral emulsions containing fat was investigated. DEHP is added to polyvinyl chloride (PVC) to impart flexibility. However, DEHP is a lipid-soluble suspected carcinogen that is hepatotoxic and teratogenic in rodents, and has been shown to leach from PVC products containing lipophilic mixtures. Consequently, total parenteral nutrition (TPN) mixtures containing fat emulsions should be stored in ethylvinyl acetate (EVA) bags rather than PVC packs. However, while TPN bags are made of EVA, they contain PVC-DEHP residues and the lines used between TPN bags and venous catheters are made of PVC-DEHP. The present study quantified the amount of DEHP leached from bags and tubing that could potentially contaminate patients during home TPN. Four types of emulsions containing fat were studied. Levels of DEHP in the bag and at the outlet tubing were measured by high-performance liquid chromatography (HPLC). This was measured during simulated TPN at different times after starting perfusion, 1 day after reconstitution of solutions in the bags, and 1 week later after storage at 4 degrees C. Detectable and stable amounts of DEHP were found to leach from bags (0.2 +/- 0.008 mg to 0.7 +/- 0.02 mg) and DEHP content increased in the outlet tubing (0.8 +/- 0.09 mg to 2 +/- 0.07 mg) during simulated infusions. The same phenomenon was observed after 1 week of storage at 4 degrees C. DEHP extraction by TPN depends on the lipid content of each TPN preparation and the flow rate. These results suggest that children treated with prolonged TPN are regularly exposed to significant amounts of DEHP.

Experimental study on infusion devices containing polyvinyl chloride: To what extent are they di(2-ethylhexyl)phthalate-free?

The use of medical devices containing highly criticized phthalates including di(2-ethylhexyl) phthalate (DEHP) has been challenged by European directive 2007/47/CE, put into effect in March 2010. New plasticizers are now being used to soften PVC in medical devices: trioctyltrimellitate (TOTM), di-isononyl-cyclohexan-1,2-dicarboxilate (DINCH) and di(2-ethylhexyl) terephthalate (DEHT). To quantify DEHP in nine DEHP-free medical devices made of PVC softened by alternative plasticizers, high performance liquid chromatography analysis with ultraviolet detection at 220 nm wavelength was achieved. An NMR spectroscopy was performed to confirm DEHP presence. Only two medical devices out of the nine tested were truly without DEHP. One of them showed traces of DEHP exceeding the threshold contamination of 0.1% in plastic mass set by REACH regulations. TOTM plasticizer is still incriminated when polyvinyl-chloride (PVC) is contaminated with DEHP. Manufacturers must verify the purity of their raw material, not only on PVC, but also on other soft plastics entering into the composition of medical infusion devices. The clinical consequences of exposure to certain levels of DEHP have not been evaluated. A solution could be to use alternative PVC-free materials.

Stability, compatibility and plasticizer extraction of quinine injection added to infusion solutions and stored in polyvinyl chloride (PVC) containers

The stability of quinine was determined in various diluents and in polyvinyl chloride (PVC) containers. The release of diethyhexyl phthalate (DEHP) from PVC bags into intravenous infusions of quinine was also measured. We used an injection of two doses of quinine; quiniforme at 500 mg and quinimax at 400 mg in either 250- or 500-ml PVC infusion bags containing 5% dextrose, to give initial nominal concentrations of 2 or 1 mg ml(-1) quiniforme and 1.6 or 0.8 mg ml(-1) quinimax, the mean concentrations commonly used in clinical practice. Samples were assayed by stability-indicating high-performance liquid chromatography (HPLC) and the clarity was determined visually. Experiments were conducted to determine whether the stability and compatibility of quinine would be compromised, and whether DEHP would be leached from PVC bags and PVC administration sets during storage and simulated infusion. There was no substantial loss of quiniforme and quinimax over 1- or 2-h simulated infusion irrespective of the diluent, and storage during 8 h at 22 degrees C, 48 or 72 h at 4 degrees C and 96 h at 45 degrees C. Leaching of DEHP was also detected during simulated infusion delivery using PVC bags and PVC administration sets. The quantity was less than 2 microg ml(-1). During storage at 4 degrees C and room temperature the leaching of DEHP was low, but when the temperature was 45 degrees C the quantity was high, 21 microg ml(-1). To minimise patient exposure to DEHP, quinine solutions with all drugs should be infused immediately or stored for a maximum of 48 h at 4 degrees C.

Leaching of diethylhexyl phthalate from PVC bags into intravenous teniposide solution

Abstract The stability of teniposide in various diluents and polyvinyl chloride bags was determined, and the extent of leaching of di(2-ethylhexyl) phthalate (DEHP) from PVC bags caused by the teniposide formulation was measured. No significant drug loss was observed during simulated infusions ( n = 4) for 1 h using PVC infusion bags and administration sets. No significant difference was found between infusion solutions (5% glucose or 0.9% Nacl). To minimize patient exposure to DEHP, teniposide solutions may be stored in a glass or polyolefin container and delivered through polyethylene-lined i.v. administration sets. If PVC bags are used for preparing teniposide solutions, the injections must be used immediately after preparation or stored 4–5 h at + 4°C.

High-performance liquid chromatographic determination of naltrexone in plasma of hemodialysis patients.

A simple, sensitive, selective and reliable reversed-phase high-performance liquid chromatographic (HPLC) method with UV detection is described for the determination of naltrexone in plasma samples. Naltrexone and the internal standard, naloxone, were isolated from plasma either with a liquid-liquid extraction method using ethyl acetate or with a solid-phase extraction method using Sep-Pack C18 cartridge before chromatography. The extracts were dried under a stream of nitrogen and the samples were reconstituted in the mobile phase, then 20 microL were injected on a Waters Symmetry C18 column (5 microm particle size, 4.6 x 150 mm). The mobile phase consisted of 0.06% triethylamine (pH 2.8)-acetonitrile (92:8, v/v) pumped at 1 mL/min. The peak-area ratio versus plasma concentration was linear over the range of 10-500 ng/mL and the detection limit was less than 8 ng/mL. Quantification was by ultra-violet detection at 204 nm. The present method was applied to the determination of the plasma concentration of naltrexone in dialyzed patients. Patients (n = 8) with severe generalized pruritus received 50 mg of naltrexone orally per day for 2 weeks. The variability in the therapeutic response in treated patients required plasma concentration investigations of this opioid antagonist.

Stability study of fotemustine in PVC infusion bags and sets under various conditions using a stability-indicating high-performance liquid chromatographic assay

The stability and compatibility of fotemustine, a nitrosourea anticancer agent, in 5% dextrose solution with polyvinyl chloride (PVC) containers and administration sets were studied under different conditions of temperature and light. The drug was diluted to 0.8 and 2 mg ml(-1) in 100 or 250 ml 5% dextrose injection solutions for 1-h simulated infusions using PVC bags and administration sets with protection from light. After preparation in the PVC bags containing 5% dextrose, fotemustine was also prepared at the same concentrations and stored at 4 degrees C for 48 h and at room temperature (22 degrees C) or at sunray exposure ( > 30 degrees C) over 8 h with or without protection from light. The solution samples were removed immediately at various time points of simulated infusions and storage, and stored at -20 degrees C until analysis. The physical compatibility with PVC and chemical stability in solution of fotemustine were assessed by visual examination and by measuring the concentration of the drug in duplicate using a stability-indicating high-performance chromatographic assay. When admixed with a 5% dextrose solution, fotemustine 2 and 0.8 mg ml(-1) was compatible and stable over 1-h of simulated infusion using PVC bags through PVC administration sets with protection from light. On the other hand, in the same diluent, fotemustine was compatible and stable with PVC bags for at least 8 h at 22 degrees C with protection from light and for at least 48 h at 4 degrees C with protection from light. There were no pH variation, no visual change, no color change, no visible precipitation and no loss of the drug. Conversely, when the solutions were exposed to light (ambient or solar), the drug concentration decreased rapidly, leading to the production of a degradation product as shown by mass spectral analysis and a discoloration of the solutions. Finally, in all cases, no DEHP (di-2-ethylhexyl phthalate) was detected in the injection solution.

A Routine HPLC Method for Monitoring Midazolam in Serum

A routine high-performance liquid chromatographic method for measuring midazolam in human serum has been developed. The sample preparation procedure consisted of simple liquid-liquid extraction with dichloromethane, followed by evaporation under nitrogen. The mobile phase used was a mixture of acetonitrile at 0.02 M and sodium acetate at pH 3.0 (80:20, v/v) and a flow-rate of 1.2 mL/min. The separation was performed on two cyanopropyl columns (150 x 4.6 mm). The detection was by UV absorption at 240 nm. A linear range from 10 to 1,000 ng/mL and a quantification limit of 7.4 ng/mL of serum was reached. The mean intra-assay and inter-assay reproducibility from serum sample spiked with 100 ng/mL were 4.1 and 4.7%, respectively. The recoveries from serum sample spiked with 50, 100, 500 ng/mL were 85.46, 85.38 and 85.57%, respectively. This method was developed to allow pharmacokinetics study of midazolam in young patients in short surgical interventions.

Stability and compatibility of cisplatin and carboplatin with PVC infusion bags.

The availability and compatibility of drugs from solutions infused via PVC infusion bags through PVC administration sets have been examined. No significant drug loss was observed during simulated infusions using PVC infusion bags and administration sets over time periods used in hospitals (cisplatin, 2 h; carboplatin, 1 h). The stability of carboplatin was studied in 5% dextrose. In 0.9% NaCl, we observed that carboplatin could be converted to cisplatin in the presence of chloride ions. With cisplatin, no significant difference was found between infusion solutions (5% dextrose or 0.9% NaCl). The stability of cisplatin (5% dextrose or 0.9% NaCl) and carboplatin (5% dextrose) was also studied in PVC bags after storage in the dark at room temperature. The results show that the drugs were stable over the 9‐day storage period studied.