Retrospective evaluation and prediction of clearance and toxicity of high dose methotrexate in childhood acute lymphoblastic leukemia patients

To find the predictors of High Dose Methotrexate toxicities in childhood Acute Lymphoblastic Leukemia Patients. This study included 198 Childhood Acute Lymphoblastic Leukemia patients (303 infusions) who were treated with High Dose Methotrexate. Methotrexate levels at different time point were measured by modified enzyme multiplied immunoassay technique assay. The correlation between Methotrexate levels and toxicity was evaluated by Receiver Operating Characteristic curve. When the Methotrexate level at 42 h was lower than 0.76 µmol/L, the sensitivity for predicting thorough clearance at 66 h was 90.78%. When the Methotrexate level at 42 h was higher than1.5 µmol/L, the sensitivity for predicting delayed clearance was 82.17%. When the Methotrexate level at 66 h was higher than 0.5 µmol/L, the sensitivity for predicting Methotrexate toxicity was 89.09%. When the Methotrexate level at 66 h was lower than 0.1 µmol/L, the sensitivity for predicting Methotrexate nontoxicity was 92.73%. The Methotrexate level at 42 h could be predictor for delayed clearance. The Methotrexate level at 66 h could be predictor for toxicity.

Formulation development and evaluation of colon targeted delayed release methotrexate pellets for the treatment of colonic carcinoma

Colonic carcinoma is one of the most common internal malignancies and is the second leading cause of deaths in United States. Methotrexate (MTX) is a drug of choice in the treatment of colon cancer. The aim of the present research work was to develop and characterize colon targeted pellets of MTX for treatment of colonic carcinoma. The product and process parameters were optimized by screening methods. Pellets were prepared by extrusion spheronization using microcrystalline cellulose (MCC) as spheronizing aid and ethyl cellulose (EC) as release retardant in different ratio. Based on the physical appearance, sphericity and % in vitro drug release, batch P17 containing EC: MCC (3:7) was optimized for core pellets. The site specificity was obtained by screening the coating polymers and by coating the core pellets with EudragitS100. The 32 full factorial design was applied in which airflow rate (X1) and coating time (X2) were the independent parameters and physical appearance (Y1) and time taken for 100% drug release (Y2) were selected as the dependent variables. From the results obtained, 6min of coating time and 60cm3/min airflow rate was optimized. The batch B5 showed appropriate physical appearance and % in vitro drug release upto 17hr indicating sustained release property. The ex-vivo studies performed on rat colon indicated a significant relation with the in vitro drug release. The drug release followed Higuchi's model indicating the diffusion pattern of drug release from the matrix of pellets. Thus, the coated pellets can be a good candidate for site specific delivery of MTX to colon by decreasing the gastric irritation and thus to improve bioavailability.

Protective effects of silymarin on methotrexate-induced damages in rat testes

Abstract The present study aimed to investigate the protective effects of silymarin (SMN), an antioxidant, on methotrexate (MTX)-induced damage in rat testes. Thirty-two Wistar albino rats were divided into four groups (n = 8): control, MTX (20 mg/kg, i.p. on days 1 and 5), SMN (200 mg/kg, orally), and MTX + SMN (20 mg/kg, i.p. on days 1 and 5 and SMN 200 mg/kg orally) groups. At the end of the 6-week trial period, histopathological, immunohistochemical, biochemical, and spermatological analyses were performed on testes tissues. Histopathologically, MTX-induced damage, including depletion of germ cell and loos of spermatozoa, was significantly improved with SMN treatment. Immunohistochemically, the immunoreactivity of glutathione peroxidase 1 (GPx1) and manganese superoxide dismutase 2 (SOD2) were detected more intensely in the MTX + SMN group than in the MTX group. Biochemical examinations revealed that SMN supplementation decreased the lipid peroxidation and increased enzymatic antioxidants in the SMN-treated rats. Spermatologically, significant differences were found in the density, motility, dead-to-live sperm ratio, and abnormal sperm rate in the MTX + SMN group compared to the MTX group. In conclusion, SMN seems to have protective effects as an antioxidant against MTX-induced damage in rat testes.

Validación de métodos analíticos de control de procesos de antitumorales inyectables / Analytical methods validation of processes control in injectable antitumor agents

Se validaron los métodos analíticos alternativos para el control de proceso de fluorouracilo 500 mg, doxorrubicina 50 mg y metotrexato 50 mg por espectrofotometría, por ser estos métodos màs sencillos, económicos, que permiten controlar la calidad de los medicamentos en el anàlisis de control de proceso. Las curvas de calibración del fluorouracilo, la doxorrubicina y el metotrexato, se realizaron en el intervalo de 60 al 140 por ciento, donde fueron lineales con coeficientes de correlación iguales a 0,9998; 0,9999 y 0,9999, respectivamente; la prueba estadística para el intercepto y la pendiente se consideraron no significativas. Se obtuvieron recobrados del 99,97, 99,08 y 99,35 por ciento, respectivamente en el intervalo de concentraciones estudiado, y las pruebas de Cochran y t de Student resultaron no significativas. Los coeficientes de variación de los estudios de la repetibilidad fueron inferiores al 3 por ciento para las 6 réplicas ensayadas, mientras que en los anàlisis de la precisión intermedia las pruebas de Fischer y t de Student indicaron diferencias no significativas. Los métodos resultaron específicos, lineales, precisos y exactos en el intervalo de concentraciones estudiadas.

Alternative analytical methods were validated for the process control of 500 mg florouacil, 50 mg doxorrubicin and 50 mg methotrexate by spectrophotometry because of they are more simple and economic allowint to control the drugs quality in process anaslysis control. Calibration curves of fluorouracil, doxorrubicin and methotrexate were plotted in interval from 60 to 140 percent, where there were linear with correlation coeficients similar to 0.9998, 0.9999 and 0.9999, respectively; statistical text for intercept and slope were considered as non-significant. Recoveries of 99.97, 99.98 and 99.35 percent were achieved, respectively in study concentration interval and Cochran and t-Student tests were also non-significant. Methods were specific, linear, precises and exacts in interval of study concentrations.

Estudo comparativo do mecanismo de açäo e dos efeitos farmacológicos do Tenoxicam, Indometacina, Dexametasona e Metotrexato no processo inflamatório agudo e crônico / Comparative study of mechanism of action and the farmacological effects of Tenoxican, Indomethacin, Dexamethazone and Methotrexate in acute and chronic inflammatory process

Aprofundamos o estudo dos efeitos farmacológicos da dexametasona, indometacina e tenoxicam e de uma droga citostática (metotrexano), assim como a análise dos mecanismos envolvidos na estimulaçäo flogógena causada por agentes de intensidades fraca, média e forte. Para isso, empregamos o teste edemogênico, que demonstrou serem os fármacos antiinflamatórios näo esteróides (tenoxicam e indometacina), os de maior potência na inibiçäo da exsudaçäo plasmática induzida pela paracoccidioidina. Todavia, com agentes flogógenos de intensidade média (carragenina), o metotrexano foi o medicamento mais potente, enquanto que com a placa microbiana dental (agente forte), a dexametasona e a indometacina foram os de maior potência antiinflamatória. Por meio da análise histomorfométrica relativa dos granulomas induzidos por esse último agente, verificamos até 14 dias, a maior potência antiinflamatória apresentada pelo tenoxicam, comparativamente a indometacina, pois inibiu mais acentuadamente a regiäo central de necrose supurativa, demonstrando efeito semelhante ao da dexametasona, näo obstante, em relaçäo à inibiçäo da densidade do volume do tecido granulomatoso, os fármacos mais potentes terem sido a indometacina e a dexametasona. Após os 14 dias näo foi constatada diferença significativa entre o efeito apresentado pelo tenoxicam e o da indometacina. O acentuado efeito apresentado pelos NSAIDs em relaçäo à inibiçäo da densidade de volume dos macrófagos, semelhante ao efeito do metotrexato, sugeriu que os NSATDs inibiram a proliferaçäo das células progenitoras mielóides dos monócitos/macrófagos. Também agiram tanto aumentando (21 dias) como inibindo (28 dias) a densidade de volume ocupada pelas fibras colágenas, enquanto que a dexametasona apresentou efeito contrário. Tais resultados indicaram que no processo inflamatório induzido por agentes flogógenos de intensidade forte (PMD) estimulores da acentuada produçäo Lts e PGs, o emprego de antiinflamatórios esteróides e näo esteróides foi vantajosa em relaçäo ao fármaco citostático