Pilot study: External surface contamination of gemcitabine and 5-fluorouracil on drug packaging.

INTRODUCTION: Antineoplastic drugs (ADs) are commonly used pharmaceuticals for anticancer treatments. It has previously been shown that the external surface of drug vials frequently is contaminated with ADs. More than a decade ago methods to prevent occupational exposure were introduced by using plastic coverage of the glass vials or packing vials in a secondary plastic container. The aim of the pilot study was to determine contamination levels of ADs on different parts of AD packaging of two different commercially available drug vials on the Swedish market and to investigate the occurrence of cross contamination of ADs. METHODS: Packagings of gemcitabine (GEM) and 5-fluorouracil (5-FU) were tested by wipe sampling. Five ADs; GEM, 5-FU, cyclophosphamide (CP), ifosfamide and etoposide were quantified using liquid chromatography mass spectrometry. RESULTS: AD contaminations were detected in 69% and 60% of the GEM and 5-FU packaging samples. Highest levels, up to approximately 5 µg/sample, were observed on the glass vials. The protective shrink-wrap of 5-FU vials and the plastic container of GEM were contaminated with low levels of 5-FU and GEM, respectively, and furthermore the 5-FU vials with shrink-wrap were cross-contaminated with GEM. Cross-contamination of CP and GEM was detected on 5-FU vials with plastic shrink-wrap removed. CONCLUSIONS: External contamination of ADs are still present at primary drug packagings on the Swedish market. Protection of AD vials by plastic shrink-wrap or a secondary plastic container does not remove the external contamination levels completely. The presence of cross contamination of ADs on drug packagings was also observed.

Four-year follow-up of surface contamination by antineoplastic drugs in a compounding unit.

OBJECTIVES: This study aimed to monitor the contamination by antineoplastic drugs on work surfaces in a compounding unit 4 years after its implementation. METHODS: This descriptive study was done in a unit performing on average 45 000 preparations per year. Surface sampling points (N=23) were monitored monthly in the frame of routine activity from the opening of an anticancer drug compounding unit. Contamination with nine antineoplastic drugs (cyclophosphamide, ifosfamide, dacarbazine, 5-fluorouracil, methotrexate, gemcitabine, cytarabine, irinotecan and doxorubicin) was assessed on wipes with a local liquid chromatography coupled with a tandem mass spectrometer analysis. The contamination rate (CR, %) was prospectively monitored every month during the entire study period. The occurrence of critical incidents was also registered. The effect of each safety measure implemented during this period was also analysed. RESULTS: Based on the 1104 samples collected between March 2016 and March 2020, the CR was 18.5%. If three different critical incidents among a vial breakage that occurred were individually considered, this CR was slightly lower than that in the literature. Eight months after opening and taking different corrective actions, the overall CR dropped from 42.39% to 11.52% (p<0.001). Contamination was limited to the area that includes the compounding room and, more precisely, the welder and the QC-Prep+ sampling points. CONCLUSIONS: From the beginning of the study and from month to month, surface contamination was limited to the nearest sampling points to the compounding unit. This 4-year monitoring study allowed us to determine the intravenous conventional antineoplastic drugs and sampling points to be focused on.

Evaluation of long-term data on surface contamination by antineoplastic drugs in pharmacies.

PURPOSE: The handling of antineoplastic drugs represents an occupational health risk for employees in pharmacies. To minimize exposure and to evaluate cleaning efficacy, wipe sampling was used to analyze antineoplastic drugs on surfaces. In 2009, guidance values were suggested to facilitate the interpretation of results, leading to a decrease in surface contamination. The goal of this follow-up was to evaluate the time trend of surface contamination, to identify critical antineoplastic drugs and sampling locations and to reassess guidance values. METHODS: Platinum, 5-fluorouracil, cyclophosphamide, ifosfamide, gemcitabine, methotrexate, docetaxel and paclitaxel were analyzed in more than 17,000 wipe samples from 2000 to 2021. Statistical analysis was performed to describe and interpret the data. RESULTS: Surface contaminations were generally relatively low. The median concentration for most antineoplastic drugs was below the limit of detection except for platinum (0.3 pg/cm2). Only platinum and 5-fluorouracil showed decreasing levels over time. Most exceedances of guidance values were observed for platinum (26.9%), cyclophosphamide (18.5%) and gemcitabine (16.6%). The most affected wipe sampling locations were isolators (24.4%), storage areas (17.6%) and laminar flow hoods (16.6%). However, areas with no direct contact to antineoplastic drugs were also frequently contaminated (8.9%). CONCLUSION: Overall, the surface contaminations with antineoplastic drugs continue to decrease or were generally at a low level. Therefore, we adjusted guidance values according to the available data. The identification of critical sampling locations may help pharmacies to further improve cleaning procedure and reduce the risk of occupational exposure to antineoplastic drugs.

Validation of chemotherapy drug vapor containment of an air cleaning closed-system drug transfer device.

PURPOSE: The purpose of this study was to test the efficacy of ChemfortTM, an air filtration closed-system drug transfer device to prevent release of chemotherapy drug vapors and aerosols under extreme conditions. The air cleaning system is based on the adsorption of drug vapors by an activated carbon filter in the Vial Adaptor before the air is released out of the drug vial. The functionality of the carbon filter was also tested at the end of device's shelf life, and after a contact period with drug vapors for 7 days. Cyclophosphamide and 5-fluorouracil were the chemotherapy drugs tested. METHODS: The Vial Adaptor was attached to a drug vial and both were placed in a glass vessel. A needle was punctured through the vessel stopper and the Vial Adaptor septum to allow nitrogen gas to flow into the vial and to exit the vial via the air filter into the glass vessel which was connected to a cold trap. Potential contaminated surfaces in the trap system were wiped or rinsed to collect the escaped drug. Samples were analyzed using liquid chromatography tandem mass spectrometry. RESULTS: Cyclophosphamide and 5-fluorouracil were detected on most surfaces inside the trap system for all Vial Adaptors without an activated carbon filter. Contamination did not differ between the Vial Adaptors with and without membrane filter indicating no effect of the membrane filter. The results show no release of either drug for the Vial Adaptors with an activated carbon filter even after 3 years of simulated aging and 7 days of exposure to drug vapors. CONCLUSIONS: Validation of air cleaning CSTDs is important to secure vapor and aerosol containment of chemotherapy and other hazardous drugs. The presented test method has proven to be appropriate for the validation of ChemfortTM Vial Adaptors. No release of cyclophosphamide and 5- fluorouracil was found even for Vial Adaptors after 3 years of simulated aging and 7 days of exposure to drug vapors.

Evaluation of external contamination on the vial surfaces of some hazardous drugs that commonly used in Chinese hospitals and comparison between environmental contamination generated during robotic compounding by IV: Dispensing robot vs. manual compounding in biological safety cabinet.

OBJECTIVES: The aims of the study were to evaluate the external contamination of hazardous drug vials used in Chinese hospitals and to compare environmental contamination generated by a robotic intelligent dispensing system (WEINAS) and a manual compounding procedure using a biological safety cabinet (BSC). METHODS: Cyclophosphamide, fluorouracil, and gemcitabine were selected as the representative hazardous drugs to monitor surface contamination of vials. In the comparative analysis of environmental contamination from manual and robotic compounding, wipe samples were taken from infusion bags, gloves, and the different locations of the BSC and the WEINAS robotic system. In this study, high-performance liquid chromatography coupled with double mass spectrometer (HPLC-MS/MS) was employed for sample analysis. RESULTS: (1) External contamination was measured on vials of all three hazardous drugs. The contamination detected on fluorouracil vials was the highest with an average amount up to 904.33 ng/vial, followed by cyclophosphamide (43.51 ng/vial), and gemcitabine (unprotected vials of 5.92 ng/vial, protected vials of 0.66 ng/vial); (2) overall, the environmental contamination induced by WEINAS robotic compounding was significantly reduced compared to that by manual compounding inside the BSC. Particularly, compared with manual compounding, the surface contamination on the infusion bags during robotic compounding was nearly nine times lower for cyclophosphamide (10.62 ng/cm2 vs 90.43 ng/cm2), two times lower for fluorouracil (3.47 vs 7.52 ng/cm2), and more than 23 times lower for gemcitabine (2.61 ng/cm2 vs 62.28 ng/cm2). CONCLUSIONS: The external contamination occurred extensively on some hazardous drug vials that commonly used in Chinese hospitals. Comparison analysis for both compounding procedures revealed that robotic compounding can remarkably reduce environmental contamination.

A quantitative LC-MS method to determine surface contamination of antineoplastic drugs by wipe sampling.

The main objective was to develop a wipe sampling test to measure surface contamination of the most frequently used antineoplastic drugs (ADs) in Swedish healthcare and, furthermore, to develop an analysis method sensitive enough to assess low levels of contamination. Two wipe sampling tests with separate sample processing methods assessing (i) cyclophosphamide (CP), ifosfamide (IF), 5-fluorouracil (5-FU), etoposide (ETO), gemcitabine (GEM) and cytarabine (CYT) (Wipe Test 1); and (ii) GEM, CYT and methotrexate (MTX) (Wipe Test 2), respectively, were developed by optimization of absorption and extraction efficiencies using different wipe tissue materials, tissue wetting solution, and extraction solvents. A fast liquid chromatography tandem mass spectrometry method was developed for simultaneous detection of the studied ADs. The limit of quantification for the method was between 0.04 to 2.4 ng/wipe sample (0.10 to 6.1 pg/cm2 for an area of 400 cm2) and at 50 ng/sample the within-day precision was between 1.3 and 15%, and the accuracy between 102 and 127%. Wipe Test 1 was applied in an assessment of cleaning efficiency of five different cleaning solutions (formic acid, water, sodium hydroxide, ethanol, and sodium dodecyl sulfate (SDS) for removal of ADs from surfaces made of stainless steel or plastic. For CP, IF, 5-FU, GEM, and CYT 92% of the AD were removed regardless of surface and cleaning solution. In conclusion, a user-friendly assessment method to measure low levels of seven ADs in the work environment was developed and validated. Assessment of the decontamination efficiency of cleaning solutions concerning removal of ADs from stainless steel showed that efficiencies differed depending on the AD with water being the least effective cleaning agent. The results suggests that a combination of different cleaning agents including detergent and a solution with an organic component would be optimal to efficiently remove the measured ADs from surfaces in the workplace.

Quality control of cytostatic drug preparations-comparison of workflow and performance of Raman/UV and high-performance liquid chromatography coupled with diode array detection (HPLC-DAD).

The drugs used for treatment during chemotherapy are manufactured individually for each patient in specialised pharmacies. Thorough quality control to confirm the identity of the delivered active pharmaceutical ingredient and the final concentration of the prepared application solution is not standardized yet except for optical or gravimetric testing. However, solution stability problems, counterfeit drugs, and erroneous or deliberate underdosage may occur and negatively influence the quality of the product and could cause severe health risks for the patient. To take a step towards analytical quality control, an on-site analytical instrument using Raman and UV absorption spectroscopy was employed and the results were compared to high-performance liquid chromatography coupled to diode array detection. Within the scope of the technology evaluation, the uncertainty of measurement was determined for the analysis of the five frequently used cytostatic drugs 5-fluorouracil, cyclophosphamide, gemcitabine, irinotecan and paclitaxel. The Raman/UV technique (2.0-3.2% uncertainty of measurement; level of confidence: 95%) achieves a combined uncertainty of measurement comparable to HPLC-DAD (1.7-3.2% uncertainty of measurement; level of confidence: 95%) for the substances 5-fluorouracil, cyclophosphamide and gemcitabine. However, the uncertainty of measurement for the substances irinotecan and paclitaxel is three times higher when the Raman/UV technique is used. This is due to the fact that the Raman/UV technique analyses the undiluted sample; therefore, the sample has a higher viscosity and tendency to foam. Out of 136 patient-specific preparations analysed within this study, 96% had a deviation of less than 10% from the target content.

Occupational exposure to antineoplastic drugs: what about hospital sanitation personnel?

OBJECTIVE: Occupational exposure to antineoplastic drugs (ANPs) occurs mainly through dermal contact. Our study was set up to assess the potential exposure of hospital sanitation (HS) personnel, for whom almost no data are available, through contamination of surfaces they regularly touch. METHODS: In the oncology departments of two hospitals around Montreal, surface wipe samples of 120-2000 cm2 were taken at 10 sites cleaned by the HS personnel and five other sites frequently touched by nursing and pharmacy personnel. A few hand wipe samples were collected to explore skin contamination. Wipes were analyzed by ultra-performance liquid chromatography tandem-mass spectrometry for 10 ANPs. RESULTS: Overall, 60.9% of 212 surface samples presented at least one ANP above the limits of detection (LOD). Cyclophosphamide and gemcitabine were most often detected (52% and 31% of samples respectively), followed by 5-fluorouracil and irinotecan (15% each). Highest concentrations of five ANPs were found in outpatient clinics on toilet floors (5-fluorouracil, 49 ng/cm2; irinotecan, 3.6 ng/cm2), a perfusion pump (cyclophosphamide, 19.6 ng/cm2) and on a cytotoxic waste bin cover (gemcitabine, 4.97 ng/cm2). Floors in patient rooms had highest levels of cytarabine (0.12 ng/cm2) and methotrexate (6.38 ng/cm2). Hand wipes were positive for two of 12 samples taken on HS personnel, seven of 18 samples on nurses, and two of 14 samples on pharmacy personnel. CONCLUSIONS: A notable proportion of surfaces showed measurable levels of ANPs, with highest concentrations found on surfaces cleaned by HS personnel, who would benefit from appropriate preventive training. As potential sources of worker exposure, several hospital surfaces need to be regularly monitored to evaluate environmental contamination and efficacy of cleaning.

Evaluation of decontamination efficacy of four antineoplastics (ifosfamide, 5-fluorouracil, irinotecan, and methotrexate) after deliberate contamination.

The main objective was to determine the decontamination efficacy of quaternary ammonium, 0.1% sodium hypochlorite, and water after deliberate contamination with four antineoplastics (ifosfamide, 5-fluorouracil, irinotecan, methotrexate). A stainless-steel surface was deliberately contaminated with ifosfamide (15 µg), 5-fluorouracil (10 µg), irinotecan (1 µg), and methotrexate (1 µg). First, a single decontamination step with either water, quaternary ammonium, or 0.1% sodium hypochlorite was tested. Then, the effect of up to four successive decontamination steps with either quaternary ammonium or 0.1% sodium hypochlorite was tested. Commercial wipes consisting of two layers of non-woven microfibers with an inner layer of highly absorbent viscose fibers were used. Triplicate surface samples were obtained and tested by ultra-performance liquid chromatography tandem mass spectrometry. The limits of detection were 0.004 ng/cm2 for ifosfamide, 0.040 ng/cm2 for 5-fluorouracil, 0.003 ng/cm2 for irinotecan, and 0.002 ng/cm2 for methotrexate. After a single decontamination step, the 0.1% sodium hypochlorite eliminated 100% of contamination with 5-fluorouracil, irinotecan, and methotrexate and 99.6 ± 0.5% of ifosfamide contamination. Quaternary ammonium and water also removed 100% of the 5-fluorouracil, and 99.5% to 99.9% of the other three antineoplastics. For ifosfamide, irinotecan, and methotrexate, the decontamination efficacy increased with successive decontamination steps with quaternary ammonium. 5-fluorouracil was undetectable after a single decontamination step. Methotrexate was the only drug for which decontamination efficacy was less than 100% after four decontamination steps. 100% decontamination efficacy was achieved from the decontamination step with 0.1% sodium hypochlorite for 5-fluorouracil, irinotecan, and methotrexate. For ifosfamide, 100% efficacy was achieved only after the third decontamination step. It was possible to make all traces of antineoplastic undetectable after deliberate contamination with 5-fluorouracil, irinotecan, and methotrexate with a 0.1% chlorine solution; up to three decontamination steps were needed to make ifosfamide undetectable. Water or quaternary ammonium removed more than 99.5% of deliberate contamination. In several scenarios, it was necessary to repeat the decontamination to eliminate residual traces. More work is needed to identify the optimal decontamination approach for all of the antineoplastic drugs used.

Determination of 5-fluorocytosine, 5-fluorouracil, and 5-fluorouridine in hospital wastewater by liquid chromatography-mass spectrometry.

Chemotherapeutics are pharmaceutical compounds the occurrence of which in the environment is of growing concern because of the increase in treatments against cancer diseases. They can reach the aquatic ecosystems after passing through wastewater treatment plants without complete removal. One of the most frequently used chemotherapeutics is 5-fluorouracil which exhibits a strong cytostatic effect. In this paper, an analytical methodology was developed, validated, and applied to determine 5-fluorouracil, its precursor, 5-fluorocytosine, and its major active metabolite, 5-fluorouridine, in hospital wastewater samples. Due to the expected low concentrations after dilution and interferences present in such a complex matrix, a very selective and sensitive detection method is required. Moreover, an extraction method must be implemented prior to the determination in order to purify the sample extract and preconcentrate the target analytes at micrograms per liter concentration levels. Solid-phase extraction followed by liquid chromatography with tandem mass spectrometry was the combination of choice and all included parameters were studied. Under optimized conditions for wastewater samples analysis, recoveries from 63 to 108% were obtained, while intraday and interday relative standard deviations never exceeded 20 and 25%, respectively. Limits of detection between 61 and 620 ng/L were achieved. Finally, the optimized method was applied to samples from hospital wastewater effluents.

Quantification of healthcare workers' exposure to cyclophosphamide, ifosfamide, methotrexate, and 5-fluorouracil by 24-h urine assay: A descriptive pilot study.

PURPOSE: The objective of this pilot study was to determine the frequency of urination and the concentration of four hazardous drugs (cyclophosphamide, ifosfamide, methotrexate, and fluorouracil) in workers' 24-h urine samples in relation to exposure to traces with hazardous drugs. METHODS: The study was conducted in three healthcare centers in the region of Montréal, Quebec, Canada. We recruited healthcare workers (nurses and pharmacy technicians) assigned to the hematology-oncology department. Each participant was asked to collect all urine voided during a 24-h period, to fill out an activity journal documenting tasks performed and to document the use of personal protective equipment. Samples were analyzed for cyclophosphamide, ifosfamide, methotrexate, and alpha-fluoro-beta-alanine (FBAL, the main urinary metabolite of 5-fluorouracil). Drugs were quantified by ultra-performance liquid chromatography-tandem mass spectrometry (positive electrospray MRM mode). RESULTS: Eighteen healthcare workers (10 nurses and 8 technicians) were recruited and provided consent to participate. Urine samples were obtained between 1 September and 30 September 2019. The number of urinations over the 24-h collection period ranged from 3 to 11 per participant. A total of 128 urine samples were analyzed for the 18 workers. All urine samples were negative for the four antineoplastics tested. CONCLUSION: No traces of cyclophosphamide, ifosfamide, methotrexate, or FBAL were found in the 24-h urine samples of 18 healthcare workers practicing in three healthcare facilities in Quebec. Although it was feasible to collect 24-h urine samples in this research project, it appears unrealistic to do so recurrently as part of a large-scale surveillance program.

High-throughput method to analyze tegafur and 5-fluorouracil in human tears and plasma using hydrophilic interaction liquid chromatography/tandem mass spectrometry.

RATIONALE: We developed a new high-throughput method to analyze tegafur (FT) and 5-fluorouracil (5-FU) in tear and plasma samples using hydrophilic interaction liquid chromatography (HILIC)/tandem mass spectrometry (MS/MS). METHODS: The tear samples (10 µL) spiked with FT, 5-FU, and 5-chlorouracil (internal standard) were diluted using 40 µL of 2 M ammonium acetate and 250 µL of acetonitrile with 2% formic acid; 20 µL of plasma spiked with the two drugs and internal standard was diluted with 80 µL of 2 M ammonium acetate and 500 µL of acetonitrile with 2% formic acid. After centrifugation, the clear supernatant extract (15 µL) was directly injected into the HILIC/MS/MS instrument, and each drug was separated on a Unison UK-Amino column (50 mm × 3 mm i.d., 3 µm particle size) with a linear gradient elution system composed of 10 mM ammonium acetate (pH 6.8) and acetonitrile at a flow rate of 0.7 mL/min. We performed quantification by multiple reaction monitoring (MRM) with negative-ion atmospheric-pressure chemical ionization. RESULTS: Distinct peaks were observed for the drugs on each MRM channel within 2 min. The regression equations showed good linearity within the range 0.04-4.0 µg/mL for the tear and plasma samples with detection limits at 0.02-0.04 µg/mL. Recoveries for target analytes (FT and 5-FU) for the tear and plasma samples were in the 94-128% and 94-104% ranges, respectively. The intra- and inter-day coefficients of variation for the two drugs were lower than 10.8%. The accuracies of quantitation were 97-115% for both samples. CONCLUSIONS: We established a high-throughput, reproducible, and practical procedure for analyzing FT and 5-FU in human tear and plasma samples using HILIC/MS/MS analysis with an aminopropyl-bonded mixed-mode separation column. This method can be applied to the high-throughput routines used in clinical analyses.

Therapeutic drug monitoring (TDM) of 5-fluorouracil (5-FU): new preanalytic aspects.

Background 5-Fluorouracil (5-FU) is frequently used for the treatment of gastrointestinal tumors. The pharmacological effect of 5-FU is influenced by genetic polymorphisms as well as differently dosed regimens. Currently, 5-FU is generally administered as a continuous infusion via an implanted port system using a body surface area (BSA)-based dose calculation. In order to optimize treatment, the area under the curve (AUC) can be estimated to allow for individual dose adjustment. A 5-FU AUC range between 20 and 30 [mg×h×L] is recommended. The aim of the current study was to assess if blood for AUC analysis could also be drawn at the side where the port system had been placed. Methods We collected EDTA blood samples of patients receiving infusional 5-FU simultaneously from different sampling points (right/left cubital vein). 5-FU concentrations were measured in a steady-state equilibrium based on nanoparticle immunoassay (My5-FU; Saladax). Results A total of 39 patients took part in this study. About half of the patients did not reach the target 5-FU concentration window (37% were under- and 16% of the patients were overdosed). Calculated median AUC was 23.3 for the right arm (range 5.8-59.4) and a median of 23.4 for the left arm (range 5.3-61.0). AUC values showed no difference between right compared to left arms (p=0.99). Conclusions In all, these results confirm that a high percentage of patients are not treated with 5-FU doses reaching suggested AUC levels of 20-30. The location of venepuncture, however, had no impact on the results of plasma 5-FU concentration.

Development of a low-cost electrochemical sensor based on babassu mesocarp (Orbignya phalerata) immobilized on a flexible gold electrode for applications in sensors for 5-fluorouracil chemotherapeutics.

There are increasing concerns regarding the risks arising from the contamination of manipulators of antineoplastic drugs promoted by occupational exposure or even in the dosage of drugs. The present work proposes the use of an electrochemical sensor based on a biopolymer extracted from the babassu coconut (Orbignya phalerata) for the determination of an antineoplastic 5-fluorouracil (5-FU) drug as an alternative for the monitoring of these drugs. In order to reduce the cost of this sensor, a flexible gold electrode (FEAu) is proposed. The surface modification of FEAu was performed with the deposition of a casting film of the biopolymer extracted from the babassu mesocarp (BM) and modified with phthalic anhydride (BMPA). The electrochemical activity of the modified electrode was characterized by cyclic voltammetry (CV), and its morphology was observed by atomic force microscopy (AFM). The FEAu/BMPA showed a high sensitivity (8.8 µA/µmol/L) and low limit of detection (0.34 µmol/L) for the 5-FU drug in an acid medium. Electrochemical sensors developed from the babassu mesocarp may be a viable alternative for the monitoring of the 5-FU antineoplastic in pharmaceutical formulations, because in addition to being sensitive to this drug, they are constructed of a natural polymer, renewable, and abundant in nature. Graphical abstract ᅟ.

Pharmacokinetics of S-1 monotherapy in plasma and in tears for gastric cancer patients.

BACKGROUND: S-1 is an oral anticancer drug composed of tegafur (FT), which is a prodrug of 5-FU, 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate. Recently, some studies have been reported on watering eyes caused by S-1. However, the mechanism of watering eyes caused by S-1 is still unclear. The aim of this study was to investigate the correlation between tears and plasma concentrations of FT, 5-FU, and CDHP, which are components and active modulator of S-1. METHODS: We prospectively investigated the pharmacokinetics (PK) of FT, 5-FU, and CDHP in plasma and in tears of gastric cancer patients who were treated with S-1 monotherapy at the dose of 80 mg/m2/day. Plasma and tears from both eyes were obtained 1, 2, 4, and 8 h after S-1 administration on day 1 and 14 of the first cycle. RESULTS: Total of eight patients were enrolled. All the FT, 5-FU and CDHP were detected both in plasma and in tears, and their PK parameters were measured. There was a positive correlation between the concentrations of FT, 5-FU and CDHP in the plasma and those in the tears on day 1 and day 14 (correlation coefficients r, right eye/left eye: r = 0.882/0.878, 0.877/0.890, and 0.885/0.878, respectively). CONCLUSION: There was a positive correlation between the concentrations of FT, 5-FU and CDHP in the plasma and those in the tears. The result is expected to facilitate the further investigation into the causes of watering eyes and the establishment of the effective methods for the prevention and the treatment.

Field evaluation of onsite near real-time monitors for surface contamination by 5-fluorouracil.

OBJECTIVES: In order to produce near real-time onsite results to detect surface contamination by antineoplastic drugs, the National Institute for Occupational Safety and Health developed monitors for 5-fluorouracil, which use surface wiping and lateral flow immunoassay for measurement. The monitors were tested in the laboratory to assess the sensitivity of detection on laboratory-produced contaminated surfaces. A field evaluation to assess the capability of the monitors to make measurements in healthcare workplaces was carried out in collaboration with a medical device company and the results are presented in this report. METHODS: The 5-fluorouracil monitor was evaluated in areas where oncology drugs were prepared and administered to patients at five different hospitals. The levels of contamination measured with the monitors were compared to levels measured with liquid chromatography-tandem mass spectrometry. RESULTS: The 5-fluorouracil values measured with the liquid chromatography-tandem mass spectrometry ranged from 0 to over 200,000 ng/100 cm2. Measurements by the 5-fluorouracil monitors in the range 10-100 ng/100 cm2 correlated with the liquid chromatography-tandem mass spectrometry. Receiver operating characteristic curves developed for the data indicated that a positive limit of 22 ng/100 cm2 would give an acceptable level of false-positives while retaining most true-positive samples. If the liquid chromatography-tandem mass spectrometry measured greater than 100 ng/100 cm2, then the monitors also measured levels greater than 100 ng/100 cm2 for the majority of samples. CONCLUSION: The data indicate that there are many areas in hospitals that are contaminated with 5-fluorouracil and the monitors will be useful in identifying this contamination.

Fluorescent copper nanoclusters as a nano-dye for DNA methyltransferase activity analysis and inhibitor screening.

Fluorescent copper nanoslusters (CuNCs) as a new class of fluorophores have attracted more and more attention due to their ease of synthesis, excellent optical properties, and low cost. In this study, a novel label-free fluorescent method was developed for the detection of DNA methyltransferases based on template length-dependent of dsDNA-CuNCs. In the absence of DNA adenine methylation methyltransferase (Dam MTase), the dsDNA containing the methylation-responsive sequence could effectively template the formation of fluorescent CuNCs with bright fluorescence. When the dsDNA substrate is methylated by Dam MTase, the methylation-sensitive restriction endonuclease Dpn I cleaves the methylated dsDNA and produces shorter dsDNA product, which fails to template fluorescent CuNCs. So, the Dam MTase activity could be identified by the changes of CuNCs' fluorescence. Based on this method, a linear range of 0.5-10 U/mL was achieved with high sensitivity and selectivity. Moreover, we also demonstrate the proposed method can be applied to evaluation and screening of inhibitors for Dam MTase.

Closed-system drug-transfer devices plus safe handling of hazardous drugs versus safe handling alone for reducing exposure to infusional hazardous drugs in healthcare staff.

BACKGROUND: Occupational exposure to hazardous drugs can decrease fertility and result in miscarriages, stillbirths, and cancers in healthcare staff. Several recommended practices aim to reduce this exposure, including protective clothing, gloves, and biological safety cabinets ('safe handling'). There is significant uncertainty as to whether using closed-system drug-transfer devices (CSTD) in addition to safe handling decreases the contamination and risk of staff exposure to infusional hazardous drugs compared to safe handling alone. OBJECTIVES: To assess the effects of closed-system drug-transfer of infusional hazardous drugs plus safe handling versus safe handling alone for reducing staff exposure to infusional hazardous drugs and risk of staff contamination. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, OSH-UPDATE, CINAHL, Science Citation Index Expanded, economic evaluation databases, the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov to October 2017. SELECTION CRITERIA: We included comparative studies of any study design (irrespective of language, blinding, or publication status) that compared CSTD plus safe handling versus safe handling alone for infusional hazardous drugs. DATA COLLECTION AND ANALYSIS: Two review authors independently identified trials and extracted data. We calculated the risk ratio (RR) and mean difference (MD) with 95% confidence intervals (CI) using both fixed-effect and random-effects models. We assessed risk of bias according to the risk of bias in non-randomised studies of interventions (ROBINS-I) tool, used an intracluster correlation coefficient of 0.10, and we assessed the quality of the evidence using GRADE. MAIN RESULTS: We included 23 observational cluster studies (358 hospitals) in this review. We did not find any randomised controlled trials or formal economic evaluations. In 21 studies, the people who used the intervention (CSTD plus safe handling) and control (safe handling alone) were pharmacists or pharmacy technicians; in the other two studies, the people who used the intervention and control were nurses, pharmacists, or pharmacy technicians. The CSTD used in the studies were PhaSeal (13 studies), Tevadaptor (1 study), SpikeSwan (1 study), PhaSeal and Tevadaptor (1 study), varied (5 studies), and not stated (2 studies). The studies' descriptions of the control groups were varied. Twenty-one studies provide data on one or more outcomes for this systematic review. All the studies are at serious risk of bias. The quality of evidence is very low for all the outcomes.There is no evidence of differences in the proportion of people with positive urine tests for exposure between the CSTD and control groups for cyclophosphamide alone (RR 0.83, 95% CI 0.46 to 1.52; I² = 12%; 2 studies; 2 hospitals; 20 participants; CSTD: 76.1% versus control: 91.7%); cyclophosphamide or ifosfamide (RR 0.09, 95% CI 0.00 to 2.79; 1 study; 1 hospital; 14 participants; CSTD: 6.4% versus control: 71.4%); and cyclophosphamide, ifosfamide, or gemcitabine (RR not estimable; 1 study; 1 hospital; 36 participants; 0% in both groups).There is no evidence of a difference in the proportion of surface samples contaminated in the pharmacy areas or patient-care areas for any of the drugs except 5-fluorouracil, which was lower in the CSTD group than in the control (RR 0.65, 95% CI 0.43 to 0.97; 3 studies, 106 hospitals, 1008 samples; CSTD: 9% versus control: 13.9%).The amount of cyclophosphamide was lower in pharmacy areas in the CSTD group than in the control group (MD -49.34 pg/cm², 95% CI -84.11 to -14.56, I² = 0%, 7 studies; 282 hospitals, 1793 surface samples). Additionally, one interrupted time-series study (3 hospitals; 342 samples) demonstrated a change in the slope between pre-CSTD and CSTD (3.9439 pg/cm², 95% CI 1.2303 to 6.6576; P = 0.010), but not between CSTD and post-CSTD withdrawal (-1.9331 pg/cm², 95% CI -5.1260 to 1.2598; P = 0.20). There is no evidence of difference in the amount of the other drugs between CSTD and control groups in the pharmacy areas or patient-care areas.None of the studies report on atmospheric contamination, blood tests, or other measures of exposure to infusional hazardous drugs such as urine mutagenicity, chromosomal aberrations, sister chromatid exchanges, or micronuclei induction.None of the studies report short-term health benefits such as reduction in skin rashes, medium-term reproductive health benefits such as fertility and parity, or long-term health benefits related to the development of any type of cancer or adverse events.Five studies (six hospitals) report the potential cost savings through the use of CSTD. The studies used different methods of calculating the costs, and the results were not reported in a format that could be pooled via meta-analysis. There is significant variability between the studies in terms of whether CSTD resulted in cost savings (the point estimates of the average potential cost savings ranged from (2017) USD -642,656 to (2017) USD 221,818). AUTHORS' CONCLUSIONS: There is currently no evidence to support or refute the routine use of closed-system drug transfer devices in addition to safe handling of infusional hazardous drugs, as there is no evidence of differences in exposure or financial benefits between CSTD plus safe handling versus safe handling alone (very low-quality evidence). None of the studies report health benefits.Well-designed multicentre randomised controlled trials may be feasible depending upon the proportion of people with exposure. The next best study design is interrupted time-series. This design is likely to provide a better estimate than uncontrolled before-after studies or cross-sectional studies. Future studies may involve other alternate ways of reducing exposure in addition to safe handling as one intervention group in a multi-arm parallel design or factorial design trial. Future studies should have designs that decrease the risk of bias and enable measurement of direct health benefits in addition to exposure. Studies using exposure should be tested for a relevant selection of hazardous drugs used in the hospital to provide an estimate of the exposure and health benefits of using CSTD. Steps should be undertaken to ensure that there are no other differences between CSTD and control groups, so that one can obtain a reasonable estimate of the health benefits of using CSTD.

Use and handling safety of Mini-Spike 2® chemo and puresite for safe chemotherapy compounding in a hospital pharmacy.

We wanted to evaluate the impact of Mini-Spike 2® Chemo + Puresite (MSCP) use on contamination surface levels, professionals' satisfaction and compounding time at pharmacy compared with Phaseal™. Presence of cyclophosphamide (CYP) and 5-fluorouracil (5FU) was evaluated at three sampling times: baseline; after a decontamination procedure and six months after MSCP use for CYP and 5FU compounding. Testing was carried out using an independent laboratory and wipe testing kit. To test compounding time, four different nurses followed the same compounding protocol with each device. We also developed a questionnaire to obtain feedback from the nurses. We did not find statistically significant differences in the median contamination surface levels between basal and final sampling time, CYP (0.140; 95% CI -1.135, 1.601), 5FU (-0.506; 95% CI -1.756, 0.287). We observed a difference of 10 s on compounding times between the two devices tested (p < 0.001) favoring MSCP. Finally, eight nurses answered the survey, with the best valued aspect as the aspiration/injection flow and resistance, and the worst value the comfort using Puresite and valve connection. MSCP maintains low surface contamination levels in our setting assuring compounding time standards. Satisfaction survey let us know which were the major advantages and disadvantages of the device.

Pre and post intervention study of antiblastic drugs contamination surface levels at a Pharmacy Department Compounding Area using a closed system drug transfer device and a decontamination process.

Assuring healthcare workers security on Hazardous Drugs (HD) compounding is critical in healthcare settings. Our study aims to demonstrate that the use of a Close System drug Transfer Device (CSTD) PhaSeal™ added to a decontamination process reduces antiblastic surface contamination levels in the Compounding Area (CA) of our Pharmacy Department (PD). We selected cyclophosphamide, 5-fluorouracil and iphosphamide to be evaluated. Testing was carried out with a wipe kit and quantified by an independent laboratory. We defined four sampling times: baseline; just after a decontamination procedure, which was repeated weekly during the study; four months after introduction of CSTD PhaSeal™ for cyclophosphamide and 5-fluorouracil compounding; and after eight months using CSTD PhaSeal™ for cyclophosphamide and 5-fluorouracil and one month for iphosphamide compounding. There was a decrease at the number of positive samples at the beginning/end of the study for all the drugs tested: 28/15 for cyclophosphide, 29/23 for iphosphamide and 7/1 for 5-fluorouracile. Comparing to the baseline, median cyclophosphamide levels significantly decreased (p-value <0.001) at 4 and 8 months sampling time (baseline: 1.01 ng/cm2 to 0.06 ng/cm2 and 0.01 ng/cm2), and median iphosphamide levels significantly decreased (p < 0.001) at 8 months sampling time (baseline: 3.02 ng/cm2 to 0.06 ng/cm2). 5-Fluorouracil did not show significant differences between the sampling times (baseline: 0.09 ng/cm2 to 0.09 ng/cm2). We saw a significant increase at iphosphamide levels at 4 months sampling point, contrary to cyclophosphamide, which levels had decreased. The use of CSTD PhaSeal™ for iphosphamide compounding the last month was implemented for ethical reasons after this intermediate results review. Our study suggests that the use of CSTD PhaSeal™, adding to decontaminating procedures, significantly reduces antiblastic drug surface levels at the CA of our PD.