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1.
J Oncol Pharm Pract ; : 1078155221992103, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33567975

RESUMO

INTRODUCTION: Healthcare workers exposure to antineoplastic drugs can lead to adverse health effects. Guidelines promote the safe handling of antineoplastic drugs, but no safe exposure limit was determined. Regular surface sampling contributes to ensuring workers safety. METHODS: A cross-sectional monitoring is conducted once a year with voluntary Canadian centers, since 2010. Twelve standardized sampling sites were sampled. Samples were analyzed by high performance mass coupled liquid chromatography. The limits of detection (in ng/cm2) were: 0.001 for cyclophosphamide and gemcitabine; 0.3 for docetaxel and ifosfamide; 0.04 for 5-fluorouracil and paclitaxel; 0.003 for irinotecan; 0.002 for methotrexate; 0.01 for vinorelbine. RESULTS: The surfaces from 109 centers were sampled between 01/01/2020-18/06/2020. Twenty-six centers delayed their participation because of the COVID-19 pandemic. 1217 samples were analyzed. Surfaces were frequently contaminated with cyclophosphamide (34% positive, 75th percentile 0.00165 ng/cm2) and gemcitabine (16% and <0.001 ng/cm2). The armrest of patient treatment chairs (84% to at least one drug), the front grille inside the biological safety cabinet (BSC) (73%) and the floor in front of the BSC (55%) were frequently contaminated. Centers that prepared ≥5000 antineoplastic drugs annually had higher concentration of cyclophosphamide on their surfaces (p < 0.0001). Contamination measured on the surfaces was reduced from 2010 to 2020. CONCLUSIONS: This large-scale study showed reproducible long term follow up of the contamination of standardized sites of Canadian centers and a reduction in surface contamination from 2010 to 2020. Periodic surface sampling help centers meet their continuous improvements goals to reduce exposure as much as possible. The COVID-19 pandemic had a limited impact on the program.

2.
J Occup Environ Hyg ; 18(2): 43-50, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33357045

RESUMO

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.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32740538

RESUMO

OBJECTIVES: Crohn disease (CD) can affect patient's quality of life (QOL) with physical, social, and psychological impacts. This study aimed to investigate the QOL of children with CD and its relationship with patient and disease characteristics. METHODS: Children ages from 10 to 17 years with diagnosed CD for more than 6 months were eligible to this cross-sectional study conducted in 35 French pediatric centers. QOL was assessed by the IMPACT-III questionnaire. Patient and disease characteristics were collected. RESULTS: A total of 218 children (42% of girls) were included at a median age of 14 years (interquartile range [IQR]: 13--16). Median duration of CD was 3.2 years (IQR: 1.7-5.1) and 63% of children were in clinical remission assessed by wPCDAI. Total IMPACT-III score was 62.8 (±11.0). The lowest score was in "emotional functioning" subdomain (mean: 42.8 ±â€Š11.2). Clinical remission was the main independent factor associated with QOL of children with CD (5.74 points higher compared with those "with active disease", 95% confidence interval [CI] 2.77--8.70, P < 0.001). Age of patient at the evaluation was found negatively correlated with QOL (-0.76 per year, 95% CI: -1.47 to -0.06, P = 0.009). Presence of psychological disorders was associated with a lower QOL (-9.6 points lower to those without, 95% CI: -13.34 to -5.86, P < 0.0001). Total IMPACT-III and its subdomains scores were not related to sex, disease duration, or treatments. CONCLUSIONS: These results not only confirm that clinical remission is a major issue for the QOL of patients, but also highlights the importance of psychological care.

4.
J Oncol Pharm Pract ; 26(8): 1864-1870, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32138611

RESUMO

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.

5.
J Oncol Pharm Pract ; 26(8): 1921-1930, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32114883

RESUMO

INTRODUCTION: The primary objective was to describe environmental contamination with National Institute for Occupational Safety and Health Group 1 hazardous drugs in oncology pharmacies and outpatient clinics in Canada in 2019, as part of an annual surveillance project. METHODS: In each participating center, 12 standardized sites (6 in the oncology pharmacy and 6 in outpatient clinic) were sampled. Each sample was prepared to allow quantification of six antineoplastic drugs (cyclophosphamide, ifosfamide, methotrexate, gemcitabine, 5-fluorouracil, and irinotecan) by ultra-performance liquid chromatography-tandem mass spectrometry. Samples were also tested for three additional antineoplastic drugs (docetaxel, paclitaxel, and vinorelbine) without quantification. The impact of certain characteristics of the sampling sites was evaluated with a Kolmogorov-Smirnov test for independent samples. RESULTS: Ninety-three Canadian centers participated in 2019, with a total of 1045 surfaces sampled. Cyclophosphamide was the drug most often found in the surface samples (32.4% of samples with positive result), followed by gemcitabine (20.3%). The front grille inside the biological safety cabinet (81.5% of samples positive for at least one antineoplastic drug) and the armrest of a treatment chair (75.8%) were the most frequently contaminated surfaces. Centers with more oncology inpatient and outpatient beds, those that prepared more antineoplastic drugs each year, and those that used more cyclophosphamide each year had higher concentrations of cyclophosphamide contamination on the surfaces tested (p < 0.0001). CONCLUSION: Traces of dangerous drugs were found in oncology pharmacies and oncology outpatient clinics in 93 Canadian hospitals in 2019. However, the quantities measured were very small. Every healthcare worker should consider these work areas to be contaminated and should wear appropriate protective equipment.

6.
Can J Hosp Pharm ; 72(5): 377-384, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31692608

RESUMO

Background: Surfaces in health care centres are often contaminated with traces of antineoplastic drugs. Such contamination should be limited as much as possible, to reduce workers' exposure. Objectives: The primary objective was to monitor environmental contamination with 9 antineoplastic drugs in oncology pharmacy and patient care areas of Canadian health care centres. The secondary objective was to explore the use of sodium hypochlorite as a cleaning agent for cyclophosphamide contamination. Methods: This cross-sectional evaluation was conducted from January to April 2018. Twelve standardized sites were sampled at each participating centre: 6 in the oncology pharmacy and 6 in patient care areas. Six of the antineoplastic drugs (cyclophosphamide, ifosfamide, methotrexate, gemcitabine, 5-fluorouracil, and irinotecan) were quantified by ultra-performance liquid chromatography - tandem mass spectrometry. For the other 3 antineoplastic drugs (docetaxel, paclitaxel, and vinorelbine), samples were screened for contamination but not quantified. The effect of using sodium hypochlorite as a cleaning agent was evaluated with a Kolmogorov-Smirnov test for independent samples. Results: Of 202 Canadian centres invited, 79 participated. A total of 887 surface samples were analyzed, 467 from pharmacy areas and 420 from patient care areas. Cyclophosphamide was the drug most often found as a contaminant (32.2% [286/887] of samples positive, 75th percentile of measured contamination 0.0017 ng/cm2, 90th percentile 0.021 ng/cm2). The front grille inside the hood (80.8% [63/78] of samples positive for at least one antineoplastic drug), treatment chair armrest (78.9% [60/76]), storage shelf in pharmacy (61.5% [48/78]), and floor in front of the hood (60.3% [47/78]) were the most frequently contaminated surfaces. Cleaning with a sodium hypochlorite solution was highly variable. Among centres that reported using sodium hypochlorite to clean armrests on patient chairs, the concentration of cyclophosphamide was lower (0.00866 versus 0.0300 ng/cm2, p = 0.014). Conclusions: Despite growing awareness and implementation of new safe-handling guidelines, surfaces in health care centres were contaminated with traces of many antineoplastic drugs. Providing centres with attainable goals (e.g., 75th to 90th percentile relative to other similar centres) would help in identifying the sampling sites where improvements are needed and in achieving lower surface contamination.

7.
Front Physiol ; 10: 528, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118902

RESUMO

Objectives: The objective of this study was to evaluate muscular metabolic function in children with inactive juvenile idiopathic arthritis (JIA). Methods: Fifteen children with inactive JIA and fifteen healthy controls were matched by sex, biological age, and Tanner stage. Participants completed a submaximal incremental exercise test to determine their fat and carbohydrate oxidation rates. Results: Between the two groups, heart rate values and carbohydrate oxidation rates were the same, regardless of the relative intensity of exercise. Lipid oxidation rates were lower in JIA patients, regardless of the percentage of VO2 peak (p < 0.05). Respiratory exchange ratios beyond 50% of VO2 peak were higher in patients with JIA (p < 0.05). Respective maximal fat oxidation rates (MFO) for controls and children with JIA were 218.7 ± 92.2 vs. 157.5 ± 65.9 mg ⋅ min-1 (p = 0.03) and 4.9 ± 1.9 vs. 3.4 ± 1.2 mg ⋅ min-1 ⋅ kg-1 (p = 0.04). There was no difference between the two groups in heart rate, percentage of VO2 peak, or power of exercise to achieve MFO. Controls reached their MFO at an exercise power significantly higher than did JIA subjects (42.8 ± 16.8 and 31.9 ± 9.8 W, p = 0.004). Conclusion: Children with JIA show metabolic disturbance during exercise, even when the disease is considered inactive. This disturbance is seen in a lower lipid oxidation rate during submaximal exercise.

8.
Bioorg Chem ; 87: 181-190, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30901673

RESUMO

It has been very recently shown how naturally occurring oxyprenylated coumarins are effective modulators of melanogenesis. In this short communication we wish to generalize the potentialities as skin tanning or whitening agents of a wider panel of natural and semisynthetic aromatic compounds, including coumarins, cinnamic and benzoic acids, cinnamaldehydes, benzaldehyde, and anthraquinone derivatives. A total number of 43 compounds have been tested assaying their capacity to inhibit or stimulate melanin biosynthesis in cultured murine Melan A cells. The wider number of chemicals herein under investigation allowed to depict a detailed structure-activity relationship, as the following: (a) benzoic acid derivatives are slightly pigmenting agent, for which the effect is more pronounced in compounds with longer O-side chains; (b) independently from the type of substitution, cinnamic acids are able to increase melanin biosynthesis, while benzaldehydes are able to decrease it; (c) coumarins with a 3,3-dimethylallyl or shorter skeletons as substituents in position 7 are tanning agents, while coumarins with farnesyloxy groups are whitening ones; (d) double oxyprenylation in position 6 and 7 and 3,3-dimethylallyl or geranyl skeletons have slight depigmenting capacities, while farnesyl skeletons tend to marginally increase the tanning effect; (e) the presence of electron withdrawing groups (acetyl, COOH, and -Cl) and geranyl or farnesyl oxyprenylated chains respectively in positions 3 and 7 of the coumarin nucleus lead to a whitening effect, and finally (f) oxyprenylated anthraquinones have only a weak depigmenting capacity.


Assuntos
Produtos Biológicos/farmacologia , Cumarínicos/farmacologia , Aldeídos/síntese química , Aldeídos/química , Aldeídos/farmacologia , Animais , Antraquinonas/síntese química , Antraquinonas/química , Antraquinonas/farmacologia , Benzoatos/síntese química , Benzoatos/química , Benzoatos/farmacologia , Produtos Biológicos/síntese química , Produtos Biológicos/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cinamatos/síntese química , Cinamatos/química , Cinamatos/farmacologia , Cumarínicos/síntese química , Cumarínicos/química , Melaninas/análise , Melaninas/biossíntese , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade
10.
Molecules ; 24(3)2019 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-30704124

RESUMO

Umbelliprenin has recently been shown to have great potential as a skin whitening agent. Wishing to investigate the same effect in plant species known to biosynthesize this coumarin, three plants belonging to the Apiaceae family, namely Anethum graveolens L. (dill), Pimpinella anisum L. (anise), and Ferulago campestris (Besser) Grecescu (field ferula) were screened by HPLC analysis for their respective content of umbelliprenin in extracts obtained with different solvent mixtures and by maceration and ultrasound-assisted processes. EtOH was shown to be the best solvent, providing umbelliprenin yields ranging from 1.7% to 14.4% (with respect to the total amount of extract obtained). Extracts with the highest content of this farnesyloxycoumarin were then assayed as modulators of melanogenesis in cultured murine Melan A cells employing the same umbelliprenin obtained by chemical synthesis as the reference. A parallelism between the content of the coumarin and the recorded depigmenting effect (60% for the EtOH extract of F. campestris as the best value) was revealed for all plants extracts when applied at a dose of 100 µg/mL. Our results demonstrate that the same potential of umbelliprenin can be ascribed also to umbelliprenin-enriched plant extracts which reinforces enforce the widespread use of phyto-preparations for cosmetic purposes (e.g., A. graveolens).


Assuntos
Anethum graveolens/química , Apiaceae/química , Pimpinella/química , Extratos Vegetais/farmacologia , Preparações Clareadoras de Pele/farmacologia , Umbeliferonas/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Camundongos , Estrutura Molecular , Extratos Vegetais/química , Sementes/química , Preparações Clareadoras de Pele/química , Umbeliferonas/química
11.
Ann Biol Clin (Paris) ; 76(5): 545-552, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30226196

RESUMO

Fever is a frequent reason for consultation in pediatric emergency departments and raises the question of biological and radiological examinations. Rapidly obtaining the result of C-reactive protein (CRP) level is essential in front of the steady increase of the number of visits. We carried out a prospective study within the pediatric emergency department of the University Hospital of Clermont-Ferrand from January to April 2017, in order to evaluate the interest of the capillary CRP in point of care (POCT). In two periods, 68 patients (28 controls without and 40 cases with capillary CRP assayed on a Afinion® AS100) with naked fever greater than 48 hours were included. After a study of the analytical performances of Afinion® and a verification of the homogeneity and the comparability of the two groups on clinical criteria (age, sex, duration of the fever, antibiotics treatment) and biological (values of CRP), the interest of the CRP in POCT was evaluated. In the POCT group, a significant drop in the median of the emergency room consultation time (60 (IQR 33-125) versus 180 (IQR 158-208) minutes), the number of biological acts by patient (1 (IQR 1-3) versus 7 (IQR 3-8)), the global cost of biological and radiological examinations per patient (5.4 (IQR 5.4-32.6) versus 153.8 (IQR 46.9-180.4) euros), and the cost of reagents spent by the laboratory per patient (5.2 (IQR 5.2-6.4) versus 33.2 (IQR 2.3-34.2) euros). Thus, in the context of a clinical-biological partnership, the use of CRP in POCT present a practical and an economic interest.


Assuntos
Análise Química do Sangue/economia , Análise Química do Sangue/métodos , Proteína C-Reativa/análise , Capilares/química , Emergências , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Emergências/economia , Feminino , Custos de Cuidados de Saúde , Humanos , Imunoquímica/economia , Imunoquímica/métodos , Lactente , Masculino , Sistemas Automatizados de Assistência Junto ao Leito/economia , Estudos Prospectivos , Encaminhamento e Consulta/economia , Extração em Fase Sólida/economia , Extração em Fase Sólida/métodos
12.
Cancer Epidemiol Biomarkers Prev ; 27(9): 1083-1090, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29853481

RESUMO

Background: Biomarkers of tobacco exposure have a central role in studies of tobacco use and nicotine intake. The most significant exposure markers are nicotine itself and its metabolites in urine. Therefore, it is important to evaluate the performance of laboratories conducting these biomarker measurements.Methods: This report presents the results from a method performance study involving 11 laboratories from 6 countries that are currently active in this area. Each laboratory assayed blind replicates of seven human urine pools at various concentrations on three separate days. The samples included five pools blended from smoker and nonsmoker urine sources, and two additional blank urine samples fortified with pure nicotine, cotinine, and hydroxycotinine standards. All laboratories used their own methods, and all were based on some form of liquid chromatography/tandem mass spectrometry.Results: Overall, good agreement was found among the laboratories in this study. Intralaboratory precision was good, and in the fortified pools, the mean bias observed was < + 3.5% for nicotine, approximately 1.2% for hydroxycotinine, and less than 1% for cotinine (1 outlier excluded in each case). Both indirect and direct methods for analyzing the glucuronides gave comparable results.Conclusions: This evaluation indicates that the experienced laboratories participating in this study can produce reliable and comparable human urinary nicotine metabolic profiles in samples from people with significant recent exposure to nicotine.Impact: This work supports the reliability and agreement of an international group of established laboratories measuring nicotine and its metabolites in urine in support of nicotine exposure studies. Cancer Epidemiol Biomarkers Prev; 27(9); 1083-90. ©2018 AACR.


Assuntos
Biomarcadores/urina , Cotinina/análogos & derivados , Glucuronídeos/urina , Nicotina/urina , Fumar/epidemiologia , Fumar/urina , Cotinina/urina , Humanos , Valor Preditivo dos Testes , Prevalência , Reprodutibilidade dos Testes , Estados Unidos/epidemiologia
13.
Cell Mol Life Sci ; 75(20): 3817-3827, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29728713

RESUMO

Neural stem cells give rise to granule dentate neurons throughout life in the hippocampus. Upon activation, these stem cells generate fast proliferating progenitors that complete several rounds of divisions before differentiating into neurons. Although the mechanisms regulating the activation of stem cells have been intensively studied, little attention has been given so far to the intrinsic machinery allowing the expansion of the progenitor pool. The cell cycle protein Cdk6 positively regulates the proliferation of hippocampal progenitors, but the mechanism involved remains elusive. Whereas Cdk6 functions primarily as a cell cycle kinase, it can also act as transcriptional regulator in cancer cells and hematopoietic stem cells. Using mouse genetics, we show here that the function of Cdk6 in hippocampal neurogenesis relies specifically on its kinase activity. The present study also reveals a specific regulatory mechanism for Cdk6 in hippocampal progenitors. In contrast to the classical model of the cell cycle, we observe that the Cip/Kip family member p27, rather than the Ink4 family, negatively regulates Cdk6 in the adult hippocampus. Altogether, our data uncover a unique, cell type-specific regulatory mechanism controlling the expansion of hippocampal progenitors, where Cdk6 kinase activity is modulated by p27.


Assuntos
Proliferação de Células , Quinase 6 Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Animais , Quinase 2 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/genética , Inibidor de Quinase Dependente de Ciclina p18/deficiência , Inibidor de Quinase Dependente de Ciclina p18/genética , Inibidor de Quinase Dependente de Ciclina p27/genética , Giro Denteado/metabolismo , Giro Denteado/patologia , Hipocampo/citologia , Hipocampo/metabolismo , Hipocampo/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutagênese Sítio-Dirigida , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurogênese
14.
J Expo Sci Environ Epidemiol ; 28(5): 461-469, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29296002

RESUMO

Given that prenatal exposure to tobacco smoke can lead to increased risks of adverse health effects, having valid measures of exposure is important. In a Canadian cohort (n = 2000), maternal and infant biospecimens were analysed for cotinine. Sensitivity and specificity of self-reported active smoking status were estimated. Regression modelling was used to identify potential predictors of maternal and infant plasma cotinine in non-smoking women. During the first trimester, 60.6% of the women reported never smoking, 27.3% were former smokers, 6.1% had quit when they found out they were pregnant, 5.8% were smokers and 42% of the non-smokers reported exposure to secondhand smoke (SHS). Low detection of tobacco biomarkers in meconium limited its ability to identify exposure to SHS. The sensitivity and specificity for self-reported smoking during the 1st trimester were 85.37 and 99.45%, respectively. The lowest sensitivity was found in participants with the highest level of education and income, oldest women and those born outside Canada. Non-smoking women living in an apartment had 1.7 times higher odds of detectable plasma cotinine than those living in a single home after adjusting for other variables. Our results suggest that while self-reports are fairly accurate, they may be less so in populations with higher socio-economic status. This investigation underscores the need to consider the participant socio-economic characteristics and dwelling type when using questionnaires to estimate active and passive tobacco exposure.


Assuntos
Cotinina/sangue , Mecônio/química , Fumar/sangue , Poluição por Fumaça de Tabaco/análise , Adulto , Biomarcadores , Canadá/epidemiologia , Feminino , Humanos , Exposição Materna , Gravidez , Primeiro Trimestre da Gravidez , Gestantes , Estudos Prospectivos , Análise de Regressão , Fumar/epidemiologia , Fatores Socioeconômicos , Inquéritos e Questionários , Adulto Jovem
15.
J Oncol Pharm Pract ; 24(1): 9-17, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27799608

RESUMO

Context Oncology workers are occupationally exposed to antineoplastic drugs. This exposure can induce adverse health effects. In order to reduce their exposure, contamination on surfaces should be kept as low as possible. Objectives To monitor environmental contamination with cyclophosphamide, ifosfamide, and methotrexate in oncology pharmacy and patient care areas in Canadian hospitals. To describe the impact of some factors that may limit contamination. Methods This is a descriptive study. Twelve standardized sites were sampled in each participating center (six in the pharmacy and six in patient care areas). Samples were analyzed for the presence of cyclophosphamide, ifosfamide, and methotrexate by ultra-performance liquid chromatography tandem mass spectrometry technology. Descriptive statistical analyses were done and results were compared with a Kolmogorov-Smirnov test for independent samples. Results In 2015, 48 hospitals participated in this study (48/202, 24%). Overall, 34% (181/525) of the samples were positive for cyclophosphamide, 8% (41/525) for ifosfamide, and 6% (31/525) for methotrexate. The 75th percentile value of cyclophosphamide surface concentration was 6.9 pg/cm2. For ifosfamide and methotrexate, they were lower than the limit of detection. Centers who prepared more antineoplastic drugs per year and centers who used more cyclophosphamide per year showed significantly higher surface contamination ( p < 0.0001). Over the years, we observed a reduction in surface contamination. Conclusion In comparison with other multicenter studies that were conducted in Canada, the concentration of antineoplastic drugs measured on surfaces is decreasing. Regular environmental monitoring is a good practice in order to maintain contamination as low as reasonably achievable.


Assuntos
Antineoplásicos/análise , Monitoramento Ambiental , Exposição Ocupacional/análise , Canadá , Cromatografia Líquida , Ciclofosfamida/análise , Monitoramento Ambiental/métodos , Hospitais , Humanos , Ifosfamida/análise , Metotrexato/análise
16.
Nat Commun ; 8(1): 1903, 2017 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-29199269

RESUMO

Dendrogenin A (DDA) is a newly discovered cholesterol metabolite with tumor suppressor properties. Here, we explored its efficacy and mechanism of cell death in melanoma and acute myeloid leukemia (AML). We found that DDA induced lethal autophagy in vitro and in vivo, including primary AML patient samples, independently of melanoma Braf status or AML molecular and cytogenetic classifications. DDA is a partial agonist on liver-X-receptor (LXR) increasing Nur77, Nor1, and LC3 expression leading to autolysosome formation. Moreover, DDA inhibited the cholesterol biosynthesizing enzyme 3ß-hydroxysterol-Δ8,7-isomerase (D8D7I) leading to sterol accumulation and cooperating in autophagy induction. This mechanism of death was not observed with other LXR ligands or D8D7I inhibitors establishing DDA selectivity. The potent anti-tumor activity of DDA, its original mechanism of action and its low toxicity support its clinical evaluation. More generally, this study reveals that DDA can direct control a nuclear receptor to trigger lethal autophagy in cancers.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Colestanóis/farmacologia , Imidazóis/farmacologia , Leucemia Mieloide Aguda , Receptores X do Fígado/efeitos dos fármacos , Melanoma , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Agonismo Parcial de Drogas , Expressão Gênica/efeitos dos fármacos , Células HEK293 , Células HL-60 , Humanos , Técnicas In Vitro , Receptores X do Fígado/metabolismo , Melanoma Experimental , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Proteínas de Membrana Transportadoras/genética , Camundongos , Proteínas Associadas aos Microtúbulos/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/efeitos dos fármacos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética
17.
Mol Cell Neurosci ; 82: 126-136, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28506637

RESUMO

Thiamine is essential for normal brain function and its deficiency causes metabolic impairment, specific lesions, oxidative damage and reduced adult hippocampal neurogenesis (AHN). Thiamine precursors with increased bioavailability, especially benfotiamine, exert neuroprotective effects not only for thiamine deficiency (TD), but also in mouse models of neurodegeneration. As it is known that AHN is impaired by stress in rodents, we exposed C57BL6/J mice to predator stress for 5 consecutive nights and studied the proliferation (number of Ki67-positive cells) and survival (number of BrdU-positive cells) of newborn immature neurons in the subgranular zone of the dentate gyrus. In stressed mice, the number of Ki67- and BrdU-positive cells was reduced compared to non-stressed animals. This reduction was prevented when the mice were treated (200mg/kg/day in drinking water for 20days) with thiamine or benfotiamine, that were recently found to prevent stress-induced behavioral changes and glycogen synthase kinase-3ß (GSK-3ß) upregulation in the CNS. Moreover, we show that thiamine and benfotiamine counteract stress-induced bodyweight loss and suppress stress-induced anxiety-like behavior. Both treatments induced a modest increase in the brain content of free thiamine while the level of thiamine diphosphate (ThDP) remained unchanged, suggesting that the beneficial effects observed are not linked to the role of this coenzyme in energy metabolism. Predator stress increased hippocampal protein carbonylation, an indicator of oxidative stress. This effect was antagonized by both thiamine and benfotiamine. Moreover, using cultured mouse neuroblastoma cells, we show that in particular benfotiamine protects against paraquat-induced oxidative stress. We therefore hypothesize that thiamine compounds may act by boosting anti-oxidant cellular defenses, by a mechanism that still remains to be unveiled. Our study demonstrates, for the first time, that thiamine and benfotiamine prevent stress-induced inhibition of hippocampal neurogenesis and accompanying physiological changes. The present data suggest that thiamine precursors with high bioavailability might be useful as a complementary therapy in several neuropsychiatric disorders.


Assuntos
Hipocampo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Tiamina Pirofosfato/farmacologia , Tiamina/análogos & derivados , Tiamina/metabolismo , Animais , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Modelos Animais de Doenças , Quinase 3 da Glicogênio Sintase/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/metabolismo , Hipocampo/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Tiamina/farmacologia
18.
J Oncol Pharm Pract ; 23(5): 323-332, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27084515

RESUMO

Purpose There are health risks to workers occupationally exposed to antineoplastic drugs. We hypothesized that implementing a biological monitoring program would be feasible. The goal was to present the results of our pilot cross-sectional study of biological monitoring of four antineoplastic drugs. Methods We recruited workers from the hematology-oncology department and control workers in a mother-child university health center. This study was preceded by an information period during which we aimed at enhancing the workers' awareness and knowledge of the risks of occupational exposure. Participants filled out a journal containing activities performed and personal protective equipment worn. One urine sample was collected at the end of their shift. Samples were analyzed by UPLC/MS-MS for the presence of cyclophosphamide, ifosfamide, methotrexate, and alpha-fluoro-beta-alanine (5-fluorouracile's main urinary metabolite). Results The participation rate was 85.7% (102/119). No urine sample had detectable concentrations of any of the four drugs evaluated (0/101; 0/74 nurses, 0/11 pharmacists, 0/9 pharmacy technicians, and 0/7 doctors). In the 5 days before sampling, 67/92 (72.8%) hematology-oncology participants performed at least one activity with antineoplastic drugs. Nurses wore all of the recommended protection for technical activities (86.2%), but rarely for non-technical activities (14.9%). Pharmacists and pharmacy technicians wore all of the recommended protection for all activities (100.0%). Conclusions This pilot study had a good participation rate. The absence of positive samples was a good indication that the measures in place ensured workers' safety, even though we found areas where the worker protection can be enhanced.


Assuntos
Antineoplásicos/urina , Monitoramento Ambiental/métodos , Pessoal de Saúde , Exposição Ocupacional/análise , Adulto , Canadá , Estudos Transversais , Ciclofosfamida/urina , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Ifosfamida/urina , Masculino , Metotrexato/urina , Pessoa de Meia-Idade , Exposição Ocupacional/prevenção & controle , Equipamento de Proteção Individual/estatística & dados numéricos , Projetos Piloto , Espectrometria de Massas em Tandem , Adulto Jovem , beta-Alanina/análogos & derivados , beta-Alanina/urina
19.
Can J Hosp Pharm ; 70(6): 407-414, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29298999

RESUMO

Background: Several studies have compared cleaning procedures for decontaminating surfaces exposed to antineoplastic drugs. All of the cleaning products tested were successful in reducing most of the antineoplastic drug quantities spilled on surfaces, but none of them completely removed residual traces. Objective: To assess the efficacy of various cleaning solutions for decontaminating a biological safety cabinet workbench exposed to a defined amount of cyclophosphamide. Methods: In this pilot study, specific areas of 2 biological safety cabinets (class II, type B2) were deliberately contaminated with a defined quantity of cyclophosphamide (10 µg or 107 pg). Three cleaning solutions were tested: quaternary ammonium, sodium hypochlorite 0.02%, and sodium hypochlorite 2%. After cleaning, the cyclophosphamide remaining on the areas was quantified by wipe sampling. Each cleaning solution was tested 3 times, with cleaning and wipe sampling being performed 5 times for each test. Results: A total of 57 wipe samples were collected and analyzed. The average recovery efficiency was 121.690% (standard deviation 5.058%). The decontamination efficacy increased with the number of successive cleaning sessions: from 98.710% after session 1 to 99.997% after session 5 for quaternary ammonium; from 97.027% to 99.997% for sodium hypochlorite 0.02%; and from 98.008% to 100% for sodium hypochlorite 2%. Five additional cleaning sessions performed after the main study (with detergent and sodium hypochlorite 2%) were effective to complete the decontamination, leaving no detectable traces of the drug. Conclusions: All of the cleaning solutions reduced contamination of biological safety cabinet workbenches exposed to a defined amount of cyclophosphamide. Quaternary ammonium and sodium hypochlorite (0.02% and 2%) had mean efficacy greater than 97% for removal of the initial quantity of the drug (107 pg) after the first cleaning session. When sodium hypochlorite 2% was used, fewer cleaning sessions were required to complete decontamination. Further studies should be conducted to identify optimal cleaning strategies to fully eliminate traces of hazardous drugs.

20.
Can J Hosp Pharm ; 68(4): 279-89, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26327701

RESUMO

BACKGROUND: Occupational exposure to hazardous drugs may lead to adverse reproductive effects. There is no safe exposure limit for health care professionals. OBJECTIVES: To monitor levels of cyclophosphamide, ifosfamide, and methotrexate contamination in oncology pharmacy and patient care areas in Canadian health care institutions. METHODS: The study was conducted in 2014. Hospitals with at least 50 acute care beds were invited to participate. At each participating centre, 12 standardized sites (6 in pharmacy areas and 6 in patient care areas) were sampled. The samples were analyzed for the presence of cyclophosphamide, ifosfamide, and methotrexate by ultra-performance liquid chromatography tandem mass spectrometry technology. The limits of detection were 0.36 pg/cm(2) for cyclophosphamide, 0.95 pg/cm(2) for ifosfamide, and 0.97 pg/cm(2) for methotrexate. Descriptive statistical analyses were performed to determine the median, 75th percentile, and maximum levels. RESULTS: Fifty-one hospitals participated in this descriptive study, and a total of 584 samples were quantified. Overall, 294 (50%) of the samples were positive for cyclophosphamide, 125 (21%) for ifosfamide, and 54 (9%) for methotrexate. The most frequently contaminated sampling sites in pharmacy areas were the front grille inside the hood and the floor in front of the hood and, in patient care areas, the armrest and outpatient clinic counter. The 75th percentiles for surface concentration were 10.8 pg/cm(2) for cyclophosphamide, 1.59 pg/cm(2) for ifosfamide, and below the limit of detection for methotrexate. CONCLUSIONS: Relative to 3 other multicentre studies conducted in Quebec over the past few years, the proportion of positive samples remained constant. Nonetheless, the 75th percentile surface concentration of antineoplastic drugs has been decreasing and seems to have reached a plateau. Local (country-specific or region-specific) and attainable goals for surface contamination with hazardous drugs should be set annually, so long as no health-based limit is known.

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