RESUMO
WHAT IS KNOWN AND OBJECTIVE: Use of cisplatin can induce type I hypersensitivity reactions that may also be linked to the quality of the drug utilized. We observed cases of hypersensitivity that appeared to be associated with the brand of cisplatin used. The aim of this study was to compare two different brands of cisplatin in relation to type I hypersensitivity reactions. METHODS: Brand A was used in a tertiary care teaching hospital until 2012, and use of brand B started from January 2013, when the first hypersensitivity cases were observed. Patients were categorized based on symptom. Cisplatin of both brands was analysed by high-performance liquid chromatography (HPLC) and high-resolution electrospray ionization mass spectrometry (ESI-(+)-MS) and characterized according to US Pharmacopeia. RESULTS AND DISCUSSION: There were no cases of hypersensitivity associated with the use of cisplatin brand A, whereas four of 127 outpatients that used cisplatin brand B were affected. The two brands were in accordance with the US Pharmacopeia parameters, and there was no significant difference in the total platinum levels between the two brands when analysed by HPLC. However, high-resolution ESI-(+)-MS analyses show that brand B contains approximately 2.7 times more hydrolysed cisplatin than brand A. WHAT IS NEW AND CONCLUSION: The increase in the hydrolysed form of cisplatin found in brand B may be the cause of the hypersensitivity reaction observed in a subset of patients. We present the first study of the quality of drugs by high-resolution ESI-(+)-MS. Drug regulatory agencies and manufacturers should consider including measurement of hydrolysed cisplatin as a quality criterion for cisplatin formulations.
Assuntos
Cisplatino/efeitos adversos , Cisplatino/química , Composição de Medicamentos/métodos , Hipersensibilidade a Drogas/etiologia , Platina/química , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Química Farmacêutica/métodos , Cromatografia Líquida de Alta Pressão/métodos , Hipersensibilidade a Drogas/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espectrometria de Massas por Ionização por Electrospray/métodosRESUMO
Beta cell destruction in type 1 diabetes (TID) is associated with cellular oxidative stress and mitochondrial pathway of cell death. The aim of this study was to determine whether oxidative stress and mitochondrial dysfunction are present in T1D model (non-obese diabetic mouse, NOD) and if they are related to the stages of disease development. NOD mice were studied at three stages: non-diabetic, pre-diabetic, and diabetic and compared with age-matched Balb/c mice. Mitochondria respiration rates measured at phosphorylating and resting states in liver and soleus biopsies and in isolated liver mitochondria were similar in NOD and Balb/c mice at the three disease stages. However, NOD liver mitochondria were more susceptible to calcium-induced mitochondrial permeability transition as determined by cyclosporine-A-sensitive swelling and by decreased calcium retention capacity in all three stages of diabetes development. Mitochondria H2O2 production rate was higher in non-diabetic, but unaltered in pre-diabetic and diabetic NOD mice. The global cell reactive oxygen species (ROS), but not specific mitochondria ROS production, was significantly increased in NOD lymphomononuclear and stem cells in all disease stages. In addition, marked elevated rates of 2',7'-dichlorodihydrofluorescein (H2DCF) oxidation were observed in pancreatic islets from non-diabetic NOD mice. Using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) and lipidomic approach, we identified oxidized lipid markers in NOD liver mitochondria for each disease stage, most of them being derivatives of diacylglycerols and phospholipids. These results suggest that the cellular oxidative stress precedes the establishment of diabetes and may be the cause of mitochondrial dysfunction that is involved in beta cell death.
Assuntos
Doenças Autoimunes/metabolismo , Diabetes Mellitus Experimental/metabolismo , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Estresse Oxidativo , Animais , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Poro de Transição de Permeabilidade Mitocondrial , Permeabilidade , Espécies Reativas de Oxigênio/metabolismoRESUMO
Mitochondrial redox imbalance has been implicated in mechanisms of aging, various degenerative diseases and drug-induced toxicity. Statins are safe and well-tolerated therapeutic drugs that occasionally induce myotoxicity such as myopathy and rhabdomyolysis. Previous studies indicate that myotoxicity caused by statins may be linked to impairment of mitochondrial functions. Here, we report that 1-h incubation of permeabilized rat soleus muscle fiber biopsies with increasing concentrations of simvastatin (1-40 µM) slowed the rates of ADP-or FCCP-stimulated respiration supported by glutamate/malate in a dose-dependent manner, but caused no changes in resting respiration rates. Simvastatin (1 µM) also inhibited the ADP-stimulated mitochondrial respiration supported by succinate by 24% but not by TMPD/ascorbate. Compatible with inhibition of respiration, 1 µM simvastatin stimulated lactate release from soleus muscle samples by 26%. Co-incubation of muscle samples with 1 mM L-carnitine, 100 µM mevalonate or 10 µM coenzyme Q10 (Co-Q10) abolished simvastatin effects on both mitochondrial glutamate/malate-supported respiration and lactate release. Simvastatin (1 µM) also caused a 2-fold increase in the rate of hydrogen peroxide generation and a decrease in Co-Q10 content by 44%. Mevalonate, Co-Q10 or L-carnitine protected against stimulation of hydrogen peroxide generation but only mevalonate prevented the decrease in Co-Q10 content. Thus, independently of Co-Q10 levels, L-carnitine prevented the toxic effects of simvastatin. This suggests that mitochondrial respiratory dysfunction induced by simvastatin, is associated with increased generation of superoxide, at the levels of complexes-I and II of the respiratory chain. In all cases the damage to these complexes, presumably at the level of 4Fe-4S clusters, is prevented by L-carnitine.
RESUMO
The aim of this work was to evaluate the antimicrobial activity of Xanthium strumarium L. leaf extracts against Staphylococcus aureus, Escherichia coli, Salmonella typhimurium, Pseudomonas aeruginosa and Clostridium perfringens, as well as to investigate the presence of the toxic compound carboxyatractyloside in different plant parts. S. aureus and C. perfringens were more sensitive to non-polar than to polar fractions, and there was no difference between extracts for the remaining bacteria. All extracts had strong antimicrobial activity against the evaluated microorganisms. Carboxyatractyloside was found in cotyledons and seeds but not in adult leaves and burrs. Thus, only Xanthium strumarium leaves in adult stage can be used for medicinal purposes.
O objetivo do presente trabalho foi avaliar a atividade antimicrobiana de extratos de folhas de Xanthium strumarium L. sobre os microrganismos Staphylococcus aureus, Escherichia coli, Salmonella thyphimurium, Pseudomonas aeruginosa e Clostridium perfringens, bem como verificar a presença do composto tóxico carboxiatractilosideo em diferentes partes da planta. As bactérias S. aureus e C. perfringens foram mais sensíveis às frações não polares do que as polares, sendo que para as outras bactérias não foi verificada diferença entre os extratos. Todos os extratos apresentaram uma forte ação antimicrobiana sobre os microrganismos avaliados. O carboxiatractilosideo foi encontrado nos cotilédones e nas sementes da planta, entretanto, não foi encontrado nas folhas em estádio adulto e na carapaça espinhosa que envolve a semente. Portanto, somente as folhas de Xanthium strumarium na fase adulta podem ser utilizadas para o uso medicinal.