RESUMEN
In this study, we have evaluated the pulmonary toxicity of intratracheally (i.t.) instilled two multi walled carbon nanotubes (MWCNT) in rats. The lungs of rats were instilled with phosphate buffered saline + 1% of Tween 80 or MWCNT or carbonyl iron or quartz particles at a dose of 0.2, 1, and 5 mg/kg b.w. Following exposure, bronchoalveolar lavage (BAL) fluid was collected from the lungs to analyze lactate dehydrogenase (LDH), alkaline phosphatase (ALP), lipid peroxidation products (MDA; malondialdehyde), and total microprotein (MTP) levels at 24 h, one week, one month, and three months post instillation periods. The lungs of particle exposed rats were also collected at the same intervals to evaluate for histopathology. Exposures of MWCNT and quartz particles to rats produced transient dose dependant increase in BAL fluid LDH, ALP, MDA, and MTP values than control at all post exposure periods. Results of lung histopathology revealed that exposure of MWCNT produced a dose dependant focal peribronchiolar lymphoid aggregates, foamy alveolar macrophage accumulation, lymphoplasmocytic infiltration, fibrosis and diffuse alveolar damage. In conclusion, instillation of MWCNT produced a greater pulmonary toxicity in rats and was comparable with that of quartz.
Asunto(s)
Pulmón/efectos de los fármacos , Pulmón/patología , Nanotubos de Carbono/efectos adversos , Animales , Líquido del Lavado Bronquioalveolar/química , Pulmón/enzimología , Lesión Pulmonar/inducido químicamente , Masculino , Nanotubos de Carbono/ultraestructura , Neumonía/inducido químicamente , Cuarzo/toxicidad , Ratas , Ratas WistarRESUMEN
The neuroprotective potential of ethanolic extract of roots of Pseudarthria viscida (L) Wight and Arn (EEPV) was investigated against beta-amyloid(25-35)-induced amnesia in mice which is a suitable animal model for Alzheimer's disease (AD). The senile plaques of beta-amyloid (Abeta) are major constituents accumulated during the progression of AD as a potent neurotoxicant. In our investigation, intracerebroventricular injection of Abeta(25-35) in mice induced the neurodegeneration, exhibited the increased time of escape latency in behavioral pattern using water maze and decreased the levels of antioxidants namley superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) and vitamin C with elevated level of acetylcholinesterase enzyme (AChE). The neuroprotective potential of EEPV was determined by behavioral pattern using water maze and biochemical parameters such as SOD, CAT and GPx and vitamin C content as well as AChE. Mice were treated with EEPV at 200 and 400 mg/kg doses for 21 days. Except control, all animals received a single injection of neurotoxicant Abeta(25-35) on 14th day. In behavioural assessment, treatment with ethanolic extract improved the cognitive function in the water maze and attenuated the elevated levels of AChE with increase in antioxidant enzymes, indicating the neuroprotection with increased levels of vitamin C. These findings suggest that ethanolic extract of P. viscida exerts anti-amnesiac effects and enhances cognitive function.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Amnesia/tratamiento farmacológico , Aprendizaje por Laberinto/efectos de los fármacos , Fármacos Neuroprotectores/administración & dosificación , Extractos Vegetales/administración & dosificación , Acetilcolinesterasa/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/patología , Amnesia/inducido químicamente , Amnesia/enzimología , Amnesia/patología , Péptidos beta-Amiloides , Animales , Antioxidantes/administración & dosificación , Conducta Animal/efectos de los fármacos , Catalasa/efectos de los fármacos , Catalasa/metabolismo , Modelos Animales de Enfermedad , Glutatión Peroxidasa/efectos de los fármacos , Glutatión Peroxidasa/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones , Superóxido Dismutasa/efectos de los fármacos , Superóxido Dismutasa/metabolismoRESUMEN
The aim of the present study was to evaluate the oxidative stress and anti-oxidant status in rat serum following intra-tracheal instillation of multi wall carbon nanotubes (MWCNT). The lungs of rats were intra-tracheally instilled with (single dose of) Phosphate-buffered saline (PBS)+1% of Tween 80 (Solvent Control) or MWCNT or carbonyl Iron (negative control) or quartz particles (positive control) at a dose of 0.2, 1 and 5 mg/kg body weight. Following exposure, the blood samples were collected at 1, 7, 30 and 90 days of post instillation of nanoparticles and different parameters were estimated to assess the oxidative stress induced by the instillation of MWCNT. Exposure of MWCNT to rats produced a significant (p<0.05) dose dependent reduction of blood total anti-oxidant capacity, glutathione, superoxide dismutase, catalase activity and increased lipid peroxidation product, (Malondialdehyde) levels than PBS+1% Tween 80 control group. This reduction in the total anti-oxidant capacity in nanotubes exposed rats indicates the reduction in anti-oxidant deference mechanisms due to the instillation of MWCNT. These results indicate that, exposure of multi wall carbon nanotubes induces oxidative stress by reducing the total anti-oxidant capacity in rats. The findings suggest possible occupational health hazard in chronic exposures.
Asunto(s)
Antioxidantes/metabolismo , Nanotubos de Carbono/toxicidad , Estrés Oxidativo/efectos de los fármacos , Animales , Catalasa/metabolismo , Glutatión/metabolismo , Exposición por Inhalación/efectos adversos , Peroxidación de Lípido/efectos de los fármacos , Pulmón/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Superóxido Dismutasa/sangreRESUMEN
AIMS: A population pharmacokinetic model was developed to describe dose-response Relationships of methotrexate (MTX) in adults with breast cancer; this is done in order to explore interindividual variability in relationships with different pathophysiological variables. METHODS: Forty-five patients receiving 122 courses of MTX (2-3 per patient) were included and data were analyzed using NONMEM software. A linear two-compartment model with linear elimination best described the data. The predictive performance was evaluated by comparing the predicted and observed concentrations and the population estimated parameters with the individual estimated parameters. RESULTS: The population pharmacokinetic parameters CL ,V1,Q, V2,K,K12 and K21 generated in NONMEM, using the FO method were 3.5 L/h,1.25 L,8.43 L/h,6.45 L, 2.8,6.74 and 1.30 h-1 respectively. No covariate had significant effects on CL and VD. CONCLUSIONS: The results of this study combine relationships between the pharmacokinetic parameters of MTX and patient covariates that may be useful for dose adjustment, with a convenient sampling procedure that may aid in optimizing cancer patient care.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacocinética , Antimetabolitos Antineoplásicos/uso terapéutico , Metotrexato/farmacocinética , Neoplasias/tratamiento farmacológico , Neoplasias/epidemiología , Adulto , Anciano , Antimetabolitos Antineoplásicos/sangre , Femenino , Humanos , India/epidemiología , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Neoplasias/sangre , Pronóstico , Distribución TisularRESUMEN
A highly sensitive, rapid assay method has been developed and validated for the simultaneous estimation of tolmetin (TMT) and MED5 in human plasma with liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in the positive-ion mode. A simple solid-phase extraction process was used to extract TMT and MED5 along with mycophenolic acid (internal standard, IS) from human plasma. Chromatographic separation was achieved with 0.2% formic acid-acetonitrile (25:75, v/v) at a flow rate of 0.50 mL/min on an X-Terra RP(18) column with a total run time of 2.5 min. The MS/MS ion transitions monitored were 258.1 â 119.0 for TMT, 315.1 â 119.0 for MED5 and 321.2 â 207.0 for IS. Method validation and clinical sample analysis were performed as per FDA guidelines and the results met the acceptance criteria. The lower limit of quantitation achieved was 20 ng/mL and the linearity was observed from 20 to 2000 ng/mL, for both the anlaytes. The intra-day and inter-day precisions were in the range 3.27-4.50 and 5.32-8.18%, respectively for TMT and 4.27-5.68 and 5.32-8.85%, respectively for MED5. This novel method has been applied to a clinical pharmacokinetic study.
Asunto(s)
Cromatografía Liquida/métodos , Glicina/análogos & derivados , Pirroles/farmacocinética , Espectrometría de Masa por Ionización de Electrospray/métodos , Espectrometría de Masas en Tándem/métodos , Tolmetina/análogos & derivados , Tolmetina/sangre , Estabilidad de Medicamentos , Glicina/sangre , Glicina/química , Glicina/farmacocinética , Humanos , Modelos Lineales , Masculino , Pirroles/química , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Tolmetina/química , Tolmetina/farmacocinéticaRESUMEN
This study evaluated the ability of the multi wall carbon nanotubes (MWCNT) to induce extra pulmonary toxicities in rats following intra-tracheal (IT) instillation of two MWCNT. Two carbon nanoparticles were instilled into the lungs of rats (0.2, 1, and 5 mg/kg b.w.) and at different post-exposure intervals, blood and organs like liver, kidney, etc. were collected. The histopathological examination of liver tissues revealed a dose-dependent periportal lymphocytic infiltration, ballooning, foamy degeneration, and necrosis at all post-instillation periods. However, examination of kidney revealed the tubular necrosis and interstitial nephritis with 5 mg/kg dose at 1 month of post-instillation of both MWCNT. These liver and kidney toxicities were further confirmed by the elevated levels of respective tissue damage biomarkers. These results suggest the extra pulmonary toxicities of these carbon nanoparticles might be due to the translocation into the liver and kidney.