Evaluation of the risk of occupational exposure to antineoplastic drugs in healthcare sector: part II - the application of the FMECA method to compare manual vs automated preparation.

Healthcare workers handling antineoplastic drugs (ADs) in preparation units run the risk of occupational exposure to contaminated surfaces and associated mutagenic, teratogenic, and oncogenic effects of those drugs. To minimise this risk, automated compounding systems, mainly robots, have been replacing manual preparation of intravenous drugs for the last 20 years now, and their number is on the rise. To evaluate contamination risk and the quality of the working environment for healthcare workers preparing ADs, we applied the Failure Mode Effects and Criticality Analysis (FMECA) method to compare the acceptable risk level (ARL), based on the risk priority number (RPN) calculated from five identified failure modes, with the measured risk level (MRL). The model has shown higher risk of exposure with powdered ADs and containers not protected by external plastic shrink film, but we found no clear difference in contamination risk between manual and automated preparation. This approach could be useful to assess and prevent the risk of occupational exposure for healthcare workers coming from residual cytotoxic contamination both for current handling procedures and the newly designed ones. At the same time, contamination monitoring data can be used to keep track of the quality of working conditions by comparing the observed risk profiles with the proposed ARL. Our study has shown that automated preparation may have an upper hand in terms of safety but still leaves room for improvement, at least in our four hospitals.

Canadian monitoring program of the surface contamination with 11 antineoplastic drugs in 124 centers.

INTRODUCTION: Occupational exposure to antineoplastic drugs can lead to long-term adverse effects on workers' health. A reproducible Canadian surface monitoring program was established in 2010. The objective was to describe contamination with 11 antineoplastic drugs measured on 12 surfaces among hospitals participating in this annual monitoring program. METHODS: Each hospital sampled six standardized sites in oncology pharmacies and six in outpatient clinics. Ultra-performance liquid chromatography coupled with tandem mass spectrometry was used for cyclophosphamide, docetaxel, doxorubicin, etoposide, 5-fluorouracil, gemcitabine, irinotecan, methotrexate, paclitaxel, and vinorelbine. Platinum-based drugs were analyzed by inductively coupled plasma mass spectrometry; this excludes inorganic platinum from the environment. Hospitals filled out an online questionnaire about their practices; a Kolmogorov-Smirnov test was used for some practices. RESULTS: One hundred and twenty-four Canadian hospitals participated. Cyclophosphamide (405/1445, 28%), gemcitabine (347/1445, 24%), and platinum (71/756, 9%) were the most frequent. The 90th percentile of surface concentration was 0.01 ng/cm² for cyclophosphamide and 0.003 ng/cm² for gemcitabine. Centers that prepared 5000 or more antineoplastic per year had higher concentrations of cyclophosphamide and gemcitabine on their surfaces (p = 0.0001). Almost half maintained a hazardous drugs committee (46/119, 39%), but this did not influence the cyclophosphamide contamination (p = 0.051). Hazardous drugs training was more frequent for oncology pharmacy and nursing staff than for hygiene and sanitation staff. CONCLUSIONS: This monitoring program allowed centers to benchmark their contamination with pragmatic contamination thresholds derived from the Canadian 90th percentiles. Regular participation and local hazardous drug committee involvement provide an opportunity to review practices, identify risk areas, and refresh training.

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.

Studies of Antioxidant and Cytotoxic Activity in Ready-to-Drink Wild Ganoderma Teas: An In Vitro Approach.

Ganoderma is a medicinally important mushroom and has been used since ancient times. However, mostly G. lucidum has been used for therapeutic purposes, in form of tea, dietary and drug supplements but other species of Ganoderma are still remaining underexploited. This study is the first approach to valorize Ganoderma teas prepared from different wild species of Ganoderma other than G. lucidum with respect to both phytochemically and therapeutically through investigation of their phytochemical, carbohydrate contents and exploring their antioxidant activity. Phytochemical contents such as phenol and flavonoids were quantified using spectrophotometry methods. The carbohydrate content of the teas was estimated by phenol sulphuric acid method. The biochemical analysis revealed the teas contained a notable amount of phenolic compounds ranging from 19.15 to 40.2 µg GAE/mg of extract and also showed significant content of flavonoids. Further, antioxidant potential in terms of DPPH and ABTS radical scavenging ability and total antioxidant capacity was also evaluated. According to the results, G. resinaceum tea showed better potential in scavenging DPPH (EC50 36 ug/mL) and ABTS radicals (EC50 3 9 ug/mL) whereas the least effect was shown for the tea of G. ahmedi. Therefore, tea showing the best results, i.e. G. resinaceum tea, was also analyzed for cytotoxicity on breast cancer cells. It was found that the tea made from G. resinaceum inhibited cellular growth and proliferation in a dose-dependent manner with maximum growth inhibition (61%) observed at the highest concentration of 2.3 mg/mL. The presence of a greater quantity of carbohydrates in G. resinaceum tea also justified the remarkable anticancer potential of the tea. Overall, our findings indicated that a few wild species of Ganoderma other than G. lucidum have great potential to be valued as a healthy beverage with immense therapeutic benefits.

Plant exosome nanovesicles (PENs): green delivery platforms.

Natural plants have been attracting increasing attention in biomedical research due to their numerous benefits. Plant exosome-derived vesicles, some of the plant's components, are small nanoscale vesicles secreted by plant cells. These vesicles are rich in bioactive substances and play significant roles in intercellular communication, information transfer, and maintaining homeostasis in organisms. They also hold promise for treating diseases, and their vesicular structures make them suitable carriers for drug delivery, with large-scale production feasible. Therefore, this paper aims to provide an overview of nanovesicles from different plant sources and their extraction methods. We also outline the biological activities of nanovesicles, including their anti-inflammatory, anti-viral, and anti-tumor properties, and systematically introduce their applications in drug delivery. These applications include transdermal delivery, targeted drug delivery, gene delivery, and their potential use in the modern food industry. This review provides new ideas and methods for future research on plant exosomes, including their empowerment by artificial intelligence and gene editing, as well as their potential application in the biomedicine, food, and agriculture industries.

Novel Cytotoxic Sesquiterpene Coumarin Ethers and Sulfur-Containing Compounds from the Roots of Ferula turcica.

Six new sesquiterpene coumarin ethers, namely turcicanol A (1), turcicanol A acetate (2), turcicanol B (3), turcica ketone (4), 11'-dehydrokaratavicinol (5), and galbanaldehyde (6), and one new sulfur-containing compound, namely turcicasulphide (7), along with thirty-two known secondary metabolites were isolated from the root of the endemic species Ferula turcica Akalin, Miski, & Tuncay through a bioassay-guided isolation approach. The structures of the new compounds were elucidated by spectroscopic analysis and comparison with the literature. Cell growth inhibition of colon cancer cell lines (COLO205 and HCT116) and kidney cancer cell lines (UO31 and A498) was used to guide isolation. Seventeen of the compounds showed significant activity against the cell lines.

The Cytotoxic Activity of Dammarane-Type Triterpenoids Isolated from the Stem Bark of Aglaia cucullata (Meliaceae).

The Aglaia genus, a member of the Meliaceae family, is generally recognized to include a number of secondary metabolite compounds with diverse structures and biological activities, including triterpenoids. Among the members of this genus, Aglaia cucullata has been reported to have unique properties and thrives exclusively in mangrove ecosystems. This plant is also known to contain various metabolites, such as flavaglines, bisamides, and diterpenoids, but there are limited reports on the isolation of triterpenoid compounds from its stem bark. Therefore, this research attempted to isolate and elucidate seven triterpenoids belonging to dammarane-type (1-7) from the stem bark of Aglaia cucullata. The isolated compounds included 20S,24S-epoxy-3α,25-dihydroxy-dammarane (1), dammaradienone (2), 20S-hydroxy-dammar-24-en-3-on (3), eichlerianic acid (4), (20S,24RS)-23,24-epoxy-24-methoxy-25,26,27-tris-nor dammar-3-one (5), 3α-acetyl-cabraleahydroxy lactone (6), and 3α-acetyl-20S,24S-epoxy-3α,25-dihydroxydammarane (7). Employing spectroscopic techniques, the chemical structures of the triterpenoids were identified using FTIR, NMR, and HRESITOF-MS. The cytotoxic activity of compounds 1-7 was tested with the PrestoBlue cell viability reagent against MCF-7 breast cancer, B16-F10 melanoma, and CV-1 normal kidney fibroblast cell lines. The results displayed that compound 5 had the highest level of bioactivity compared to the others. Furthermore, the IC50 values obtained were more than 100 µM, indicating the low potential of natural dammarane-type triterpenoids as anticancer agents. These findings provided opportunities for further studies aiming to increase their cytotoxic activities through semi-synthetic methods.

Cytotoxic Steroidal Saponins Containing a Rare Fructosyl from the Rhizomes of Paris polyphylla var. latifolia.

A phytochemical investigation of the steroidal saponins from the rhizomes of Paris polyohylla var. latifolia led to the discovery and characterization of three new spirostanol saponins, papolatiosides A-C (1-3), and nine known compounds (4-12). Their structures were established via extensive spectroscopic data analysis and chemical methods. Interestingly, compounds 1 and 2 possessed a fructosyl in their oligosaccharide moiety, which is rare in natural product and was firstly reported in family Melanthiaceae. The cytotoxicity of these saponins against several human cancer cell lines was evaluated by a CCK-8 experiment. As a result, compound 1 exhibited a significant cytotoxic effect on LN229, U251, Capan-2, HeLa, and HepG2 cancer cells with IC50 values of 4.18 ± 0.31, 3.85 ± 0.44, 3.26 ± 0.34, 3.30 ± 0.38 and 4.32 ± 0.51 µM, respectively. In addition, the result of flow cytometry analysis indicated that compound 1 could induce apoptosis of glioma cells LN229. The underlying mechanism was explored by network pharmacology and western bolt experiments, which indicated that compound 1 could induce glioma cells LN229 apoptosis by regulating the EGFR/PI3K/Akt/mTOR pathway.

Cytotoxic C-20 non-oxygenated ent-kaurane diterpenoids from Isodon wardii.

Twenty new ent-kaurane diterpenoids, wardiisins A-T (1-20), along with two previously undescribed artefactual compounds (21 and 22) and twelve known analogues (23-34), were isolated from the aerial part of Isodon wardii. Their structures were elucidated by comprehensive analysis of spectroscopic data and single-crystal X-ray diffraction, and most of them were found to bear unusual C-12 oxygenation. Compounds 4, 7, 8, 19, 20, 21 exhibited remarkable cytotoxicity against the cancer cell lines HL-60, SMMC-7721, A-549, MDA-MB-231, and SW480, with IC50 values ranging from 0.3 to 5.2 µM. Moreover, 7 was found to induce G2/M cell cycle arrest and promote apoptosis in SW480 cell lines.

Antihepatoma peptide, scolopentide, derived from the centipede scolopendra subspinipes mutilans.

BACKGROUND: Centipedes have been used to treat tumors for hundreds of years in China. However, current studies focus on antimicrobial and anticoagulation agents rather than tumors. The molecular identities of antihepatoma bioactive components in centipedes have not yet been extensively investigated. It is a challenge to isolate and characterize the effective components of centipedes due to limited peptide purification technologies for animal-derived medicines. AIM: To purify, characterize, and synthesize the bioactive components with the strongest antihepatoma activity from centipedes and determine the antihepatoma mechanism. METHODS: An antihepatoma peptide (scolopentide) was isolated and identified from the centipede scolopendra subspinipes mutilans using a combination of enzymatic hydrolysis, a Sephadex G-25 column, and two steps of high-performance liquid chromatography (HPLC). Additionally, the CCK8 assay was used to select the extracted fraction with the strongest antihepatoma activity. The molecular weight of the extracted scolopentide was characterized by quadrupole time of flight mass spectrometry (QTOF MS), and the sequence was matched by using the Mascot search engine. Based on the sequence and molecular weight, scolopentide was synthesized using solid-phase peptide synthesis methods. The synthetic scolopentide was confirmed by MS and HPLC. The antineoplastic effect of extracted scolopentide was confirmed by CCK8 assay and morphological changes again in vitro. The antihepatoma effect of synthetic scolopentide was assessed by the CCK8 assay and Hoechst staining in vitro and tumor volume and tumor weight in vivo. In the tumor xenograft experiments, qualified model mice (male 5-week-old BALB/c nude mice) were randomly divided into 2 groups (n = 6): The scolopentide group (0.15 mL/d, via intraperitoneal injection of synthetic scolopentide, 500 mg/kg/d) and the vehicle group (0.15 mL/d, via intraperitoneal injection of normal saline). The mice were euthanized by cervical dislocation after 14 d of continuous treatment. Mechanistically, flow cytometry was conducted to evaluate the apoptosis rate of HepG2 cells after treatment with extracted scolopentide in vitro. A Hoechst staining assay was also used to observe apoptosis in HepG2 cells after treatment with synthetic scolopentide in vitro. CCK8 assays and morphological changes were used to compare the cytotoxicity of synthetic scolopentide to liver cancer cells and normal liver cells in vitro. Molecular docking was performed to clarify whether scolopentide tightly bound to death receptor 4 (DR4) and DR5. qRT-PCR was used to measure the mRNA expression of DR4, DR5, fas-associated death domain protein (FADD), Caspase-8, Caspase-3, cytochrome c (Cyto-C), B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), x-chromosome linked inhibitor-of-apoptosis protein and Cellular fas-associated death domain-like interleukin-1ß converting enzyme inhibitory protein in hepatocarcinoma subcutaneous xenograft tumors from mice. Western blot assays were used to measure the protein expression of DR4, DR5, FADD, Caspase-8, Caspase-3, and Cyto-C in the tumor tissues. The reactive oxygen species (ROS) of tumor tissues were tested. RESULTS: In the process of purification, characterization and synthesis of scolopentide, the optimal enzymatic hydrolysis conditions (extract ratio: 5.86%, IC50: 0.310 mg/mL) were as follows: Trypsin at 0.1 g (300 U/g, centipede-trypsin ratio of 20:1), enzymolysis temperature of 46 °C, and enzymolysis time of 4 h, which was superior to freeze-thawing with liquid nitrogen (IC50: 3.07 mg/mL). A peptide with the strongest antihepatoma activity (scolopentide) was further purified through a Sephadex G-25 column (obtained A2) and two steps of HPLC (obtained B5 and C3). The molecular weight of the extracted scolopentide was 1018.997 Da, and the peptide sequence was RAQNHYCK, as characterized by QTOF MS and Mascot. Scolopentide was synthesized in vitro with a qualified molecular weight (1018.8 Da) and purity (98.014%), which was characterized by MS and HPLC. Extracted scolopentide still had an antineoplastic effect in vitro, which inhibited the proliferation of Eca-109 (IC50: 76.27 µg/mL), HepG2 (IC50: 22.06 µg/mL), and A549 (IC50: 35.13 µg/mL) cells, especially HepG2 cells. Synthetic scolopentide inhibited the proliferation of HepG2 cells (treated 6, 12, and 24 h) in a concentration-dependent manner in vitro, and the inhibitory effects were the strongest at 12 h (IC50: 208.11 µg/mL). Synthetic scolopentide also inhibited the tumor volume (Vehicle vs Scolopentide, P = 0.0003) and weight (Vehicle vs Scolopentide, P = 0.0022) in the tumor xenograft experiment. Mechanistically, flow cytometry suggested that the apoptosis ratios of HepG2 cells after treatment with extracted scolopentide were 5.01% (0 µg/mL), 12.13% (10 µg/mL), 16.52% (20 µg/mL), and 23.20% (40 µg/mL). Hoechst staining revealed apoptosis in HepG2 cells after treatment with synthetic scolopentide in vitro. The CCK8 assay and morphological changes indicated that synthetic scolopentide was cytotoxic and was significantly stronger in HepG2 cells than in L02 cells. Molecular docking suggested that scolopentide tightly bound to DR4 and DR5, and the binding free energies were-10.4 kcal/mol and-7.1 kcal/mol, respectively. In subcutaneous xenograft tumors from mice, quantitative real-time polymerase chain reaction and western blotting suggested that scolopentide activated DR4 and DR5 and induced apoptosis in SMMC-7721 Liver cancer cells by promoting the expression of FADD, caspase-8 and caspase-3 through a mitochondria-independent pathway. CONCLUSION: Scolopentide, an antihepatoma peptide purified from centipedes, may inspire new antihepatoma agents. Scolopentide activates DR4 and DR5 and induces apoptosis in liver cancer cells through a mitochondria-independent pathway.

Occupational Exposure to Antineoplastic Drugs in Twelve French Health Care Setting: Biological Monitoring and Surface Contamination.

Antineoplastic drugs used in the treatment of cancers have an intrinsic toxicity, because of their genotoxic, teratogenic, and carcinogenic properties. Their use is recognized as an occupational hazard for healthcare workers (HCWs) who may be exposed. The purpose of this article is to present biological- and environmental-monitoring data collected in twelve French hospitals over eight years. Urine samples were collected from a wide range of HCWs (250 participants) from pharmacy and oncology units, including physicians, pharmacists, pharmacy technicians, nurses, auxiliary nurses, and cleaners. The investigated drugs were cyclophosphamide, ifosfamide, methotrexate, and α-fluoro-ß-alanine, the main urinary metabolite of 5-fluorouracil. Wipe samples were collected from various locations in pharmacy and oncology units. More than 50% of participants, from all exposure groups, were contaminated with either drug, depending on the unit, the day, or the task performed. However, workers from oncology units were more frequently exposed than workers from pharmacy units. Significant contamination was detected on various surfaces in pharmacy and oncology units, highlighting potential sources of exposure. Risk-management measures should be implemented to reduce and maintain exposures at lowest-possible levels. In addition, regular exposure assessment, including biological and environmental monitoring, is recommended to ensure the long-term efficiency of the prevention measures.

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.

New Triterpenoids from Lansium domesticum Corr. cv kokossan and Their Cytotoxic Activity.

Lansium domesticum Corr. is a member of the Meliaceae family that is widely spread in tropical and subtropical region of Asia and America. Traditionally, the fruit of this plant has been consumed because of its sweet taste. However, the fruit peels and the seeds of this plant have been rarely utilized. The previous chemical investigation of this plant showed the presence of secondary metabolites with many biological activities, including cytotoxic triterpenoid. Triterpenoids is a class of secondary metabolites which contain thirty carbon atoms in the main skeleton. The high modification of this type of compound, including the ring opening, highly oxygenated carbons, and the degradation of its carbon chain to give the nor-triterpenoid structure, is responsible for its cytotoxic activity. In this paper, we isolated and elucidated the chemical structure of two new onoceranoid triterpenes, kokosanolides E (1) and F (2), from the fruit peels of L. domesticum Corr., along with a new tetranortriterpenoid, kokosanolide G (3), from the seeds of L. domesticum Corr. The structural determination of compounds 1-3 was undertaken through FTIR spectroscopic analysis, 1D and 2D NMR, mass spectrometry, as well as through a comparison of the chemical shifts of the partial structures of compounds 1-3 with the literature data. The cytotoxic properties of compounds 1-3 were tested against MCF-7 breast cancer cells using the MTT assay. Moderate activity was shown by compounds 1 and 3, with IC50 values of 45.90 and 18.41 µg/mL, respectively, while compound 2 showed no activity (IC50 168.20 µg/mL). For the onoceranoid-type triterpene, the high symmetrical structure of compound 1 is presumably the reason for its better cytotoxic activity compared with that of compound 2. Compound 3 showed moderate activity, mainly because of the presence of the furan ring, which, based on the literature, gives better cytotoxic activity in a tetranortriterpenoid-type structure. The findings of three new triterpenoid compounds from L. domesticum indicate the significant value of this plant as a source of new compounds.

New benzaldehyde derivatives from the fruiting bodies of Hericium erinaceus with cytotoxic activity.

Four new natural compounds named hericenone O (1), hericenone P (2), hericenone Q (3), and hericenone R (4), two of them were reported synthetically (3-4), together with eleven known compounds were isolated from the fruiting bodies of Hericium erinaceus. The chemical structures of the isolated compounds were elucidated by using NMR analysis and mass spectrometry, as well as comparisons with the reported data in the literature. The bioactivity evaluation revealed that hericenone Q showed significant cytotoxic activity against Hep-G2 with IC50 values of 23.89 µM, and against HCT-116 with IC50 values of 65.64 µM.

Residual contamination in antineoplastic drug packaging.

INTRODUCTION: The handling of antineoplastic drugs should follow strict supervision and safety rules to minimize the occupational exposure risks to professionals involved. The external surface contamination of drug vials is recognized as a health risk. So, our goal was to determine if there is residual contamination on the vials and containers surface of the antineoplastic drugs doxorubicin (DOX) and cyclophosphamide (CP). METHODS: A cross-sectional study was conducted. Samples were collected using a uniform sampling procedure on the inner surfaces of the packages/boxes and the outer surfaces of the vials. The analyzes were executed by high-performance liquid chromatography/mass spectrometry (UHPLC-MS/MS). RESULTS: A total of 209 samples were analyzed, 66 of CP and 143 of DOX. CP levels were detected in nine samples (13.63%), three were below the lower limit of quantification (LLQ) and the other six had contamination levels ranging from 1.24 to 28.04 ng/filter. DOX levels were detected in 36 samples (25.17%), two were below the LLQ and the others had levels between 1.32 and 664.84 ng/filter. The majority of samples with residual contamination were in vials (80.0%), however, boxes also showed contamination. CONCLUSIONS: The results revealed the presence of residual contamination in the vials and packages of CP and DOX drugs. Although the residues found in each sample are small, special care should be taken in the handling and disposal of the antineoplastic drugs. The use of personal protective equipment is fundamental while handling the vials and packaging of cytotoxic drugs.

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.

Anticancer drugs in wastewater and natural environments: A review on their occurrence, environmental persistence, treatment, and ecological risks.

The consumption of anticancer drugs (also known as chemotherapy drugs or antineoplastic drugs) has augmented over the last decades due to increased cancer incidence. Although there is an increasing concern about the presence of pharmaceutical compounds in natural environments and urban/domestic wastewater, anticancer drugs used in chemotherapy and anticancer medication have received less attention. In this review, the occurrence, environmental persistence, and known and potential ecological impacts of anticancer drugs is discussed. This review shows that these compounds are being increasingly detected in effluents of hospitals, influents and effluents of wastewater treatment plants, river surface water and sediments, groundwater, and even drinking water. Anticancer drugs can impact aquatic organisms such as algae, crustaceans, rotifers, and fish and may promote changes in soil and water microbial communities that may alter ecosystem functioning. Our knowledge of technologies for the removal of anticancer drugs is still limited, and these drugs can be dispersed in nature in a diffuse way in an uncontrolled manner. For this reason, an improved understanding of the presence, persistence, and ecological impacts of anticancer drugs in wastewater and natural environments is needed to help design management strategies, protect aquatic microorganisms, and mitigate potential ecological impacts.

Canadian monitoring program of the surface contamination with 11 antineoplastic drugs in 122 centers.

INTRODUCTION: Occupational exposure to antineoplastic drugs can lead to long-term adverse effects on workers' health. Environmental monitoring is conducted once a year, as part of a Canadian monitoring program. The objective was to describe contamination with 11 antineoplastic drugs measured on surfaces. METHODS: Six standardized sites in oncology pharmacy and six in outpatient clinic were sampled in each hospital. Samples were analyzed by ultra-performance liquid chromatography coupled with tandem mass spectrometry (non-platinum drugs) and by inductively coupled plasma mass spectrometry (platinum-based drugs). The limits of detection (in ng/cm2) were: 0.0006 for cyclophosphamide; 0.001 for docetaxel; 0.04 for 5-fluorouracil; 0.0004 for gemcitabine; 0.0007 for irinotecan; 0.0009 for methotrexate; 0.004 for paclitaxel, 0.009 for vinorelbine, 0.02 for doxorubicine, 0.0037 for etoposide and 0.004 for the platinum. Sub-analyses were done with a Kolmogorov-Smirnov test. RESULTS: 122 Canadian hospitals participated. Cyclophosphamide (451/1412, 32% of positive samples, 90th percentile of concentration 0.0160 ng/cm2) and gemcitabine (320/1412, 23%, 0.0036 ng/cm2) were most frequently measured on surfaces. The surfaces most frequently contaminated with at least one drug were the front grille inside the biological safety cabinet (97/121, 80%) and the armrest of patient treatment chair (92/118, 78%).The distribution of cyclophosphamide concentration was higher for centers that prepared ≥ 5000 antineoplastic drug preparations/year (p < 0.0001). CONCLUSIONS: This monitoring program allowed centers to benchmark their contamination with pragmatic contamination thresholds derived from the Canadian 90th percentiles. Problematic areas need corrective measures such as decontamination. The program helps to increase the workers' awareness.

A phenylpropanoid dimer from the leaves of Piper betle.

Phytochemical analyses of the chloroform extract of Piper betle L. var. Sanchi, Piperaceae, leaves led to the isolation of a new phenylpropanoid analogue for the first time: hydroxychavicol dimer, 2-(γ'-hydroxychavicol)-hydroxychavicol (S1), on the basis of spectroscopic data 1 D (1H and 13C) and 2 D (1H-1H COSY and HMBC) NMR, as well as ESI-MS, FT-IR, HR-ESI-MS and LC-ESI-MS. Compound S1 exhibited excellent antioxidant DPPH radical scavenging activity with IC50 values of 9.07 µg/mL, compared to ascorbic acid as a standard antioxidant drug with IC50 value of 3.41 µg/mL. Evaluation of cytotoxic activity against two human colon cancer cell lines (HT 29 and COLO-205) showed significant effect with GI50 values of 73.81 and 64.02 µmol/L, compared to Doxorubicin® as a standard cytotoxic drug with GI50 value of <10 µmol/L.

Phytochemical profiling, antidiabetic, antitumoral and cytotoxic potential of Psidium cattleianum Afzel. ex Sabine leaves of red variety.

In this study, phytochemical profiling, and antidiabetic, antitumoral and cytotoxic potential of aqueous extracts of leaves of red variety of Psidium cattleianum Afzel. ex Sabine were investigated. The extracts were obtained using a cellulase complex. The total phenolic compounds (TPC) were determined, and the individual phenolic compounds were quantified by HPLC-ESI-MS/MS. For the TPC, the amounts varied from 85.91 to 106.33 mg EAG g-1. Eighteen compounds have been identified. The compounds with the highest concentrations were gallic acid, quercetin and protocatechuic acid. Antidiabetic activity was obtained through α-amylase and α-glucosidase inhibition tests. The extract inhibited 17.94% of α-amylase activity and 73.34% of α-glucosidase activity. The antitumoral activity in cells of cutaneous melanoma (SK-MEL-28) and the cytotoxic activity was determined in peripheral blood mononuclear cells (PBMC). The cellular migration was determined for cells SK-MEL-28. Antitumoral effects on cells SK-MEL-28 were observed and the absence of cytotoxicity on the PBMCs.