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1.
Environ Int ; 133(Pt B): 105236, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31675568

RESUMO

Cytostatic drugs are compounds used to treat cancer, one of the deadliest diseases worldwide with a rising yearly incidence. However, the occurrence and concentrations of a large number of cytostatics in waters and wastewaters are unknown. Thus, this study sought to analyze the concentrations of these compounds in different aquatic environments worldwide to assess the risk that these compounds pose to aquatic organisms. The top five most monitored cytostatics in aquatic environments are fluorouracil, methotrexate, tamoxifen, ifosfamide, and cyclophosphamide. Risk quotients (RQs) based on maximum reported measured concentrations revealed that mycophenolic acid and tamoxifen pose a high risk to aquatic organisms (RQmax ≥ 1) at concentrations observed in surface waters. Moreover, methotrexate and tegafur were categorized as moderate risk compounds, and bicalutamide was found to pose a low risk. Importantly, the available analytical methodologies for the quantification of some cytostatics (e.g., cisplatin, fluorouracil, daunorubicin, imatinib, and mycophenolic acid) in water could not rule out potential risk to aquatic biota, since estimated risks for these compounds using the lowest method detection limits reported in the literature (RQ MDL) were all ≥0.01 (i.e., low risk or higher). Moreover, risks based on predicted concentrations (RQ PEC) were consistently lower than those based on measured concentrations, highlighting the importance of risk assessment based on measured values. Thus, accurate and sensitive analytical methods are crucial to identify and quantify cytostatic exposure in aquatic ecosystems in order to preserve biodiversity and ensure a safer environment.


Assuntos
Citostáticos , Água Doce/química , Medição de Risco/métodos , Poluentes Químicos da Água , Organismos Aquáticos/efeitos dos fármacos , Citostáticos/análise , Citostáticos/toxicidade , Monitoramento Ambiental/métodos , Águas Residuárias/química , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
2.
PLoS Comput Biol ; 15(11): e1007493, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31738747

RESUMO

A tumour grows when the total division (birth) rate of its cells exceeds their total mortality (death) rate. The capability for uncontrolled growth within the host tissue is acquired via the accumulation of driver mutations which enable the tumour to progress through various hallmarks of cancer. We present a mathematical model of the penultimate stage in such a progression. We assume the tumour has reached the limit of its present growth potential due to cell competition that either results in total birth rate reduction or death rate increase. The tumour can then progress to the final stage by either seeding a metastasis or acquiring a driver mutation. We influence the ensuing evolutionary dynamics by cytotoxic (increasing death rate) or cytostatic (decreasing birth rate) therapy while keeping the effect of the therapy on net growth reduction constant. Comparing the treatments head to head we derive conditions for choosing optimal therapy. We quantify how the choice and the related gain of optimal therapy depends on driver mutation, metastasis, intrinsic cell birth and death rates, and the details of cell competition. We show that detailed understanding of the cell population dynamics could be exploited in choosing the right mode of treatment with substantial therapy gains.


Assuntos
Citostáticos/farmacologia , Citotoxinas/farmacologia , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacologia , Evolução Biológica , Progressão da Doença , Humanos , Modelos Biológicos , Modelos Teóricos , Mutação , Processos Neoplásicos
3.
Exp Oncol ; 41(3): 248-253, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31569929

RESUMO

Macrophages are important effectors of innate immunity and the key component of the tumor microenvironment strongly influencing cancer disease outcome and efficiency of cancer therapy. Moreover, recent data have shown that monocytes as macrophage precursors can impact on tumor ability to progression. It's well known that although tumor-associated macrophages consist of diverse populations, in general, they have tumor-supporting activity. To change tumor-supporting state of tumor-associated macrophages toward tumor-inhibiting mode is one of prospective aims of modern cancer immunotherapy. Cytostatics seems to be possible tools to achieve this aim, because recently it has been shown that chemo- and radiotherapy possess immunomodulatory effects. Most of the findings are related to lymphocytes - T-lymphocytes and NK-cells, but not to monocyte/macrophage lineage. In the review, we have analyzed how cytostatic drugs influence the properties of monocyte/macrophage lineage cells to prospect using of chemotherapy to enhance their antitumor activity.


Assuntos
Antineoplásicos/farmacologia , Citostáticos/farmacologia , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Citostáticos/uso terapêutico , Humanos , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
4.
Cells ; 8(7)2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31319624

RESUMO

DNA damage is a ubiquitous threat endangering DNA integrity in all living organisms. Responses to DNA damage include, among others, induction of DNA repair and blocking of cell cycle progression in order to prevent transmission of damaged DNA to daughter cells. Here, we tested the effect of the antibiotic zeocin, inducing double stranded DNA breaks, on the cell cycle of synchronized cultures of the green alga Chlamydomonas reinhardtii. After zeocin application, DNA replication partially occurred but nuclear and cellular divisions were completely blocked. Application of zeocin combined with caffeine, known to alleviate DNA checkpoints, decreased cell viability significantly. This was probably caused by a partial overcoming of the cell cycle progression block in such cells, leading to aberrant cell divisions. The cell cycle block was accompanied by high steady state levels of mitotic cyclin-dependent kinase activity. The data indicate that DNA damage response in C. reinhardtii is connected to the cell cycle block, accompanied by increased and stabilized mitotic cyclin-dependent kinase activity.


Assuntos
Bleomicina/toxicidade , Chlamydomonas reinhardtii/efeitos dos fármacos , Citostáticos/toxicidade , Mutagênicos/toxicidade , Cafeína/farmacologia , Pontos de Checagem do Ciclo Celular , Chlamydomonas reinhardtii/genética , Quinases Ciclina-Dependentes/metabolismo , Quebras de DNA de Cadeia Dupla , Replicação do DNA , DNA de Plantas/efeitos dos fármacos
5.
Molecules ; 24(11)2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31185601

RESUMO

A small library of 3'-deoxy-C3'-substituted xylofuranosyl-pyrimidine nucleoside analogues were prepared by photoinduced thiol-ene addition of various thiols, including normal and branched alkyl-, 2-hydroxyethyl, benzyl-, and sugar thiols, to 3'-exomethylene derivatives of 2',5'-di-O-tert-butyldimethylsilyl-protected ribothymidine and uridine. The bioactivity of these derivatives was studied on tumorous SCC (mouse squamous carcinoma cell) and immortalized control HaCaT (human keratinocyte) cell lines. Several alkyl-substituted analogues elicited promising cytostatic activity in low micromolar concentrations with a slight selectivity toward tumor cells. Near-infrared live-cell imaging revealed SCC tumor cell-specific mitotic blockade via genotoxicity of analogue 10, bearing an n-butyl side chain. This analogue essentially affects the chromatin structure of SCC tumor cells, inducing a condensed nuclear material and micronuclei as also supported by fluorescent microscopy. The results highlight that thiol-ene chemistry represents an efficient strategy to discover novel nucleoside analogues with non-natural sugar structures as anticancer agents.


Assuntos
Citostáticos/síntese química , Citostáticos/farmacologia , Conformação Molecular , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Xilose/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dimetil Sulfóxido/farmacologia , Humanos , Concentração Inibidora 50 , Espectroscopia de Prótons por Ressonância Magnética , Compostos de Sulfidrila/química
6.
Med Pr ; 70(3): 377-391, 2019 Jun 14.
Artigo em Polonês | MEDLINE | ID: mdl-31110397

RESUMO

Poland is one of the European countries with the highest level of production of dangerous medical waste. Although in Europe the volume of produced cytotoxic and cytostatic waste (used in chemotherapy by oncological patients) has been declining for several years, in Poland a reverse trend has been observed. As this waste puts the safety of medical workers and patients at risk, special handling procedures are required to limit the harmful effect of these drugs on human health. In view of the above, the aim of the work was to present the rules of conduct with cytotoxic and cytostatic drugs, and their waste, in Poland. Med Pr. 2019;70(3):377-91.


Assuntos
Antineoplásicos , Segurança Química , Citostáticos , Citotoxinas , Eliminação de Resíduos de Serviços de Saúde , Pessoal de Saúde , Humanos , Polônia
7.
Molecules ; 24(10)2019 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-31130671

RESUMO

The increasing prevalence of drug resistant and/or high-risk cancers indicate further drug discovery research is required to improve patient outcome. This study outlines a simplified approach to identify lead compounds from natural products against several cancer cell lines, and provides the basis to better understand structure activity relationship of the natural product cephalotaxine. Using high-throughput screening, a natural product library containing fractions and pure compounds was interrogated for proliferation inhibition in acute lymphoblastic leukemia cellular models (SUP-B15 and KOPN-8). Initial hits were verified in control and counter screens, and those with EC50 values ranging from nanomolar to low micromolar were further characterized via mass spectrometry, NMR, and cytotoxicity measurements. Most of the active compounds were alkaloid natural products including cephalotaxine and homoharringtonine, which were validated as protein synthesis inhibitors with significant potency against several cancer cell lines. A generated BODIPY-cephalotaxine probe provides insight into the mode of action of cephalotaxine and further rationale for its weaker potency when compared to homoharringtonine. The steroidal natural products (ecdysone and muristerone A) also showed modest biological activity and protein synthesis inhibition. Altogether, these findings demonstrate that natural products continue to provide insight into structure and function of molecules with therapeutic potential against drug resistant cancer cell models.


Assuntos
Produtos Biológicos/farmacologia , Citostáticos/química , Citostáticos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Produtos Biológicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Descoberta de Drogas , Mepesuccinato de Omacetaxina/química , Mepesuccinato de Omacetaxina/farmacologia , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Relação Estrutura-Atividade
8.
Eur J Med Chem ; 175: 234-246, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31082766

RESUMO

Selenocyanates and diselenides are potential antitumor agents. Here we report two series of selenium derivatives related to selenocyanates and diselenides containing carboxylic, amide and imide moieties. These compounds were screened for their potency and selectivity against seven tumor cell lines and two non-malignant cell lines. Results showed that MCF-7 cells were especially sensitive to the treatment, with seven compounds presenting GI50 values below 10 µM. Notably, the carboxylic selenocyanate 8b and the cyclic imide 10a also displayed high selectivity for tumor cells. Treatment of MCF-7 cells with these compounds resulted in cell cycle arrest at S phase, increased levels of pJNK and pAMPK and caspase independent cell death. Autophagy inhibitors wortmannin and chloroquine partially prevented 8b and 10a induced cell death. Consistent with autophagy, increased Beclin1 and LC3-IIB and reduced SQSTM1/p62 levels were detected. Our results point to 8b and 10a as autophagic cell death inducers.


Assuntos
Adenilato Quinase/metabolismo , Autofagia/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Citostáticos/farmacologia , MAP Quinase Quinase 4/metabolismo , Compostos Organosselênicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Citostáticos/administração & dosagem , Citostáticos/química , Relação Dose-Resposta a Droga , Ativação Enzimática , Humanos , Compostos Organosselênicos/administração & dosagem , Compostos Organosselênicos/química , Fase S/efeitos dos fármacos
9.
Int J Mol Sci ; 20(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052191

RESUMO

Tubulins and microtubules (MTs) represent targets for taxane-based chemotherapy. To date, several lines of evidence suggest that effectiveness of compounds binding tubulin often relies on different post-translational modifications on tubulins. Among them, methylation was recently associated to drug resistance mechanisms impairing taxanes binding. The sea urchin is recognized as a research model in several fields including fertilization, embryo development and toxicology. To date, some α- and ß-tubulin genes have been identified in P. lividus, while no data are available in echinoderms for arginine methyl transferases (PRMT). To evaluate the exploiting of the sea urchin embryo in the field of antiproliferative drug development, we carried out a survey of the expressed α- and ß-tubulin gene sets, together with a comprehensive analysis of the PRMT gene family and of the methylable arginine residues in P. lividus tubulins. Because of their specificities, the sea urchin embryo may represent an interesting tool for dissecting mechanisms of tubulin targeting drug action. Therefore, results herein reported provide evidences supporting the P. lividus embryo as animal system for testing antiproliferative drugs.


Assuntos
Citostáticos/toxicidade , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Ouriços-do-Mar/efeitos dos fármacos , Testes de Toxicidade/métodos , Moduladores de Tubulina/toxicidade , Tubulina (Proteína)/metabolismo , Animais , Embrião não Mamífero/efeitos dos fármacos , Metilação , Processamento de Proteína Pós-Traducional , Ouriços-do-Mar/embriologia
10.
Int J Mol Sci ; 20(9)2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31027321

RESUMO

Juniper (Juniperus communis L.) is a northern coniferous plant generally used as a spice and for nutritional purposes in foods and drinks. It was previously reported that juniper extract (JE) affects p53 activity, cellular stress, and gene expression induced cell death in human neuroblastoma cells. Therefore, the effects of juniper on p53 and Akt signaling was examined further in A549 lung, 22RV1 and DU145 prostate, and HepG2 liver cancer cells using Western blot, confocal microscopy, and MTT analysis. We found that juniper simultaneously decreased cell viability, activated the p53 pathway, and inactivated the PI3K/Akt pathway. The p53 activation was associated with increased nuclear p53 level. Akt was dephosphorylated, and its inactivation was associated with increased levels of PHLPP1 and PHLPP2 phosphatases. Parallel increases of PARP suggest that JE decreased cell viability by activating cell death. In adtion, JE potentiated the effects of gemcitabine and 5-fluorouracil anticancer drugs. Thus, JE can activate cell death in different cancer cell lines through p53 and Akt pathways.


Assuntos
Morte Celular/efeitos dos fármacos , Citostáticos/farmacologia , Juniperus/química , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Células A549 , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Fluoruracila/farmacologia , Células Hep G2 , Humanos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteína Supressora de Tumor p53/genética
11.
Exp Parasitol ; 200: 84-91, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30954455

RESUMO

Cysteine proteases are involved in critical cell processes to the protozoa from Leishmania genus, and their inhibition is a therapeutic alternative to treat the disease. In this work, derivatives of dipeptidyl nitriles acting as reversible covalent inhibitors of cysteine proteases were studied as cytostatic agents. The proteolytic activity inside the living and lysed parasite cells was quantified using a selective substrate for cysteine proteases (Z-FR-MCA) from Leishmania amazonensis and L. infantum. The overall proteolytic activity of intact cells and even cell extracts was only marginally affected at high concentrations, with the observation of cytostatic activity and cell cycle arrest of promastigotes. However, the cytotoxic effects were only observed for infected J774 macrophages, which impaired further analysis of the amastigote infection. Therefore, the proteolytic inhibition in intact L. amazonensis and L. infantum promastigotes had no relationship to the cytostatic activity, which emphasizes that these dipeptidyl nitriles act through another mechanism of action.


Assuntos
Antiprotozoários/farmacologia , Inibidores de Cisteína Proteinase/farmacologia , Citostáticos/farmacologia , Leishmania infantum/efeitos dos fármacos , Leishmania mexicana/efeitos dos fármacos , Nitrilos/farmacologia , Animais , Antiprotozoários/química , Linhagem Celular , Inibidores de Cisteína Proteinase/química , Citostáticos/química , Fibroblastos/efeitos dos fármacos , Citometria de Fluxo , Leishmania infantum/enzimologia , Leishmania mexicana/enzimologia , Macrófagos/efeitos dos fármacos , Camundongos , Nitrilos/química
12.
Kardiologiia ; 59(4): 64-66, 2019 Apr 17.
Artigo em Russo | MEDLINE | ID: mdl-31002041

RESUMO

Understanding mechanisms of chemotherapy cardiotoxicity is an important problem due to the lack of clear understanding of its occurrence. Development of endothelial dysfunction is considered to be one of possible ways in implementation of these side effects. The analysis of endothelin-1 and e-selectin levels in 26  patients with lymphoproliferative diseases before and after the completion of the treatment program was been performed. The results of the study showed normal values of E-selectin level and increased level of endothelin-1 in the whole group of patients before treatment. After completion of chemotherapy program, in the whole group, there was a decrease of these two markers. However, values of level of endothelin-1 with vasoconstrictor effect remained high even after the end of therapy. It is imp ortant that at detailed analysis the dynamics of investigated markers in patients of older age group (median age 64 years) was associated with worsening of endothelial dysfunction.


Assuntos
Doenças Vasculares , Biomarcadores , Cardiotoxicidade , Citostáticos , Endotelina-1 , Endotélio Vascular , Humanos , Pessoa de Meia-Idade
14.
Int J Occup Med Environ Health ; 32(2): 141-159, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30896680

RESUMO

Cytostatics not only induce significant side-effects in patients treated oncologically but also pose a threat to the health of occupationally exposed healthcare workers: pharmacists, physicians, nurses and other personnel. Since the 1970s numerous reports from various countries have documented the contamination of working areas with cytostatics and the presence of drugs/metabolites in the urine or blood of healthcare employees, which directly indicates the occurrence of occupational exposure to these drugs. In Poland the significant scale of occupational exposure to cytostatics is also confirmed by the data collected in the central register of occupational carcinogens/mutagens kept by the Nofer Institute of Occupational Medicine. The assessment of occupational exposure to cytostatics and health risks constitutes employers' obligation. Unfortunately, the assessment of occupational risk resulting from exposure to cytostatics raises a number of concerns. Provisions governing the problem of workers' health protection are not unequivocal because they derive from a variety of law areas, especially in a matter of hazard classification and safety data sheets for cytostatics. Moreover, no legally binding occupational exposure limits have been set for cytostatics or their active compounds, and analytical methods for these substances airborne and biological concentrations are lacking. Consequently, the correct assessment of occupational exposure to cytostatics, the evaluation of health hazards and the development of the proper preventive strategy appear difficult. The authors of this article described and discussed the amendments to the European provisions concerning chemicals in the light of employers' obligations in the field of employees' heath protection against the consequences of exposure to cytostatics. Some modifications aimed at a more effective health protection of workers occupationally exposed to cytostatics were also proposed. Int J Occup Med Environ Health. 2019;32(2):141-59.


Assuntos
Citostáticos/efeitos adversos , Pessoal de Saúde , Exposição Ocupacional/efeitos adversos , Carcinógenos , Feminino , Substâncias Perigosas/efeitos adversos , Humanos , Masculino , Mutagênicos , Doenças Profissionais/prevenção & controle , Saúde do Trabalhador/legislação & jurisprudência , Polônia , Local de Trabalho
15.
Int J Mol Sci ; 20(5)2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30841526

RESUMO

A new simplified, epoxide-free epothilone analog was prepared incorporating an N-(2-hydroxyethyl)-benzimidazole side chain, which binds to microtubules with high affinity and inhibits cancer cell growth in vitro with nM potency. Building on this scaffold, a disulfide-linked conjugate with the purported EGFR-binding (EGFR, epidermal growth factor receptor) peptide GE11 was then prepared. The conjugate retained significant microtubule-binding affinity, in spite of the size of the peptide attached to the benzimidazole side chain. The antiproliferative activity of the conjugate was significantly lower than for the parent scaffold and, surprisingly, was independent of the EGFR expression status of cells. Our data indicate that the disulfide-based conjugation with the GE11 peptide is not a viable approach for effective tumor-targeting of highly potent epothilones and probably not for other cytotoxics.


Assuntos
Citostáticos/síntese química , Epotilonas/farmacologia , Microtúbulos/metabolismo , Peptídeos/farmacologia , Moduladores de Tubulina/síntese química , Animais , Bovinos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citostáticos/farmacologia , Epotilonas/química , Receptores ErbB/metabolismo , Células HEK293 , Humanos , Peptídeos/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacologia
16.
Molecules ; 24(6)2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30871220

RESUMO

Although BRACO19 is a potent G-quadruplex binder, its potential for clinical usage is hindered by its low selectivity towards DNA G-quadruplex over duplex. High-resolution structures of BRACO19 in complex with neither single-stranded telomeric DNA G-quadruplexes nor B-DNA duplex are available. In this study, the binding pathway of BRACO19 was probed by 27.5 µs molecular dynamics binding simulations with a free ligand (BRACO19) to a DNA duplex and three different topological folds of the human telomeric DNA G-quadruplex (parallel, anti-parallel and hybrid). The most stable binding modes were identified as end stacking and groove binding for the DNA G-quadruplexes and duplex, respectively. Among the three G-quadruplex topologies, the MM-GBSA binding energy analysis suggested that BRACO19's binding to the parallel scaffold was most energetically favorable. The two lines of conflicting evidence plus our binding energy data suggest conformation-selection mechanism: the relative population shift of three scaffolds upon BRACO19 binding (i.e., an increase of population of parallel scaffold, a decrease of populations of antiparallel and/or hybrid scaffold). This hypothesis appears to be consistent with the fact that BRACO19 was specifically designed based on the structural requirements of the parallel scaffold and has since proven effective against a variety of cancer cell lines as well as toward a number of scaffolds. In addition, this binding mode is only slightly more favorable than BRACO19s binding to the duplex, explaining the low binding selectivity of BRACO19 to G-quadruplexes over duplex DNA. Our detailed analysis suggests that BRACO19's groove binding mode may not be stable enough to maintain a prolonged binding event and that the groove binding mode may function as an intermediate state preceding a more energetically favorable end stacking pose; base flipping played an important role in enhancing binding interactions, an integral feature of an induced fit binding mechanism.


Assuntos
Acridinas/farmacologia , Citostáticos/farmacologia , DNA/química , DNA/metabolismo , Acridinas/química , Sítios de Ligação , Linhagem Celular Tumoral , Citostáticos/química , Quadruplex G , Humanos , Modelos Moleculares , Simulação de Dinâmica Molecular , Conformação de Ácido Nucleico , Solventes/química
17.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1110-1111: 124-132, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30807965

RESUMO

Cytostatic drugs are compounds used to fight cancer, which may be excreted after administration to patients, and eventually reach wastewater. Given the high incidence of cancer and the properties of drugs, the drug concentrations in water systems should be evaluated. We present the optimization, development and application of a solid phase extraction (SPE) method for the determination of eight cytostatic compounds of different classes in wastewater and seawater samples. We compared four SPE cartridges prior to their determination by Ultra-High Performance Liquid Chromatography tandem Mass Spectrometry. For wastewater samples, the Oasis HLB cartridge gave the best recoveries, which were higher than 65% in most cases, achieving limit of detections (LODs) of 1.68-103.95 ng·L-1. In seawater samples, the Bond Elut cartridge afforded the best recoveries >70%, with LODs of 0.95-5.14 ng·L-1. The optimal procedure was applied in four hospital wastewater effluent samples taken during one year, and in different influents and effluents from wastewater treatment plants and seawater from marine outfalls taken in eight campaigns during two years, in Gran Canaria island (Spain). Results showed that etoposide was present in influents of wastewater treatment plants in several months and different wastewater treatment plants and hospital effluents in the range 375.8-5141 ng·L-1, while cyclophosphamide was present in some months in effluents from only one wastewater treatment plant and hospital effluents in the range 55.94-1212 ng·L-1. Vinblastine and vincristine were detected in one sample of hospital at concentrations of 1836 ng·L-1 and 1851 ng·L-1, respectively.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Citostáticos/análise , Espectrometria de Massas em Tandem/métodos , Águas Residuárias/química , Poluentes Químicos da Água/análise , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Água do Mar/química
18.
Chem Biodivers ; 16(5): e1900024, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30793846

RESUMO

The lipophilization of ß-d-riboguanosine (1) with various symmetric as well as asymmetric ketones is described (→3a-3f). The formation of the corresponding O-2',3'-ketals is accompanied by the appearance of various fluorescent by-products which were isolated chromatographically as mixtures and tentatively analyzed by ESI-MS spectrometry. The mainly formed guanosine nucleolipids were isolated and characterized by elemental analyses, 1 H-, 13 C-NMR and UV spectroscopy. For a drug profiling, static topological polar surface areas as well as 10 logPOW values were calculated by an increment-based method as well as experimentally for the systems 1-octanol-H2 O and cyclohexane-H2 O. The guanosine-O-2',3'-ketal derivatives 3b and 3a could be crystallized in (D6 )DMSO - the latter after one year of standing at ambient temperature. X-ray analysis revealed the formation of self-assembled ribbons consisting of two structurally similar 3b nucleolipid conformers as well as integrated (D6 )DMSO molecules. In the case of 3a ⋅ DMSO, the ribbon is formed by a single type of guanosine nucleolipid molecules. The crystalline material 3b ⋅ DMSO was further analyzed by differential scanning calorimetry (DSC) and temperature-dependent polarization microscopy. Crystallization was also performed on interdigitated electrodes (Au, distance, 5 µm) and visualized by scanning electron microscopy. Resistance and amperage measurements clearly demonstrate that the electrode-bridging 3b crystals are electrically conducting. All O-2',3'-guanosine ketals were tested on their cytostatic/cytotoxic activity towards phorbol 12-myristate 13-acetate (PMA)-differentiated human THP-1 macrophages as well as against human astrocytoma/oligodendroglioma GOS-3 cells and against rat malignant neuroectodermal BT4Ca cells.


Assuntos
Citostáticos/síntese química , Guanosina/química , Lipídeos/química , Animais , Varredura Diferencial de Calorimetria , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Citostáticos/química , Citostáticos/farmacologia , Eletricidade , Humanos , Ligações de Hidrogênio , Lipídeos/síntese química , Lipídeos/farmacologia , Espectroscopia de Ressonância Magnética , Conformação Molecular , Ratos , Espectrometria de Massas por Ionização por Electrospray
19.
Eur J Pharm Sci ; 130: 181-185, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30710619

RESUMO

BACKGROUND: Compounding of cytostatic drugs requires strict aseptic procedures, while exposure to toxic drugs and repetitive manual movements should be minimized. Furthermore, reuse of vials is desirable to lower the costs. To assess if all this might be safely achieved with a robot, this study aimed at qualifying the aseptic preparation process with the robotic system APOTECAchemo. METHODS: The aseptic compounding of patient-individual cytostatic solutions was simulated with media fill simulation tests to qualify the performance according to European GMP Annex 1. The contamination in the environment was measured in critical places using settle plates, contact plates, active air sampling and particle counting. Media-fill simulation tests were prepared in 3 production batches. The second part of the study evaluated the microbiological shelf-life of commercial drug vials after repeated puncturing. On six days, fifty syringes of 15 ml media were prepared from the same 50 vials with the robot. After each preparation, vials were covered with an IVA seal upon unloading from the robot to protect them from microbiological contamination. RESULTS: No microbiological contamination was found in any of the 96 media fill preparations, nor in any of the 300 syringes that were prepared with repeated puncturing. The compounding area met class A limits, while class A criteria were not fulfilled by the contact plates and settle plates placed on the right side of the loading area. There, the average colony forming units (cfu) were 3 and 1.17, respectively, meeting class B criteria. CONCLUSIONS: Robotical compounding of cytostatic drugs with APOTECAchemo meets the microbiological requirements of the European GMP. In addition, the robot can reuse vials repeatedly and safely, thereby enabling extended usage.


Assuntos
Assepsia/métodos , Citostáticos/síntese química , Composição de Medicamentos/métodos , Contaminação de Medicamentos/prevenção & controle , Serviço de Farmácia Hospitalar/métodos , Robótica/métodos , Assepsia/instrumentação , Composição de Medicamentos/instrumentação , Fenômenos Microbiológicos , Robótica/instrumentação
20.
Ecotoxicol Environ Saf ; 172: 210-215, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30710771

RESUMO

Cytostatic drugs have become one of the greatest environmental threats. They occur in surface, ground and even drinking water. Their key emission sources are hospital effluents, municipal wastewater, as well as drug manufacturers and their effluents. These compounds are extremely stable in natural waters and they are not significantly removed during wastewater treatment, because they are resistant to biodegradation. The aim of this work was to establish possible negative effects of chosen cytostatics: bleomycin and vincristine on the three trophic levels of surface waters. A single agent acute toxicity test was conducted on representatives of the producer - an aquatic freshwater plant Lemna minor, the consumer - crustaceans Daphnia magna, and the decomposer - bacteria Pseudomonas putida. Binary mixture tests were performed according to the Concentration Addition, Response Additivity, and Independent Action models. Both substances had a different effect on the tested organisms; bleomycin could be classified as a very toxic, while vincristine as a toxic water pollutant. Half maximal effective concentration (EC50) values designed in the presented single agent acute toxicity studies are < 10 mg/L in all the tests with bleomycin as well as vincristine conducted on L. minor. In tests with vincristine performed on D. magna and P. putida EC50 > 100 mg/L. The highest toxicity is demonstrated by bleomycin towards the aquatic freshwater plant (EC50 = 0.2 mg/L). The binary mixture of the tested chemicals showed antagonistic effects of environmental concern.


Assuntos
Araceae/efeitos dos fármacos , Bleomicina/toxicidade , Citostáticos/toxicidade , Daphnia/efeitos dos fármacos , Pseudomonas putida/efeitos dos fármacos , Vincristina/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Biodegradação Ambiental , Bleomicina/química , Citostáticos/química , Cadeia Alimentar , Água Doce/química , Medição de Risco , Testes de Toxicidade Aguda , Vincristina/química , Águas Residuárias/química , Purificação da Água
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