RESUMEN
OBJECTIVE: Methotrexate (MTX) is widely administered for the treatment of various cancers. However, MTX induces male reproductive toxicity. In the current study, the effect of ozone therapy (OT) on reducing the toxic effects of MTX in the mouse testicles has been investigated. METHODS: Twenty-four mice were divided into four groups: control, OT (4 mg/kg ozone), MTX (20 mg/kg), and MTX + OT. Testosterone levels, histological changes, and oxidative stress biomarkers were assessed to evaluate the protective effects of OT. RESULTS: The results demonstrated that MTX disrupted germinal epithelium, reduced serum testosterone levels, and enhanced oxidative stress in testicular tissue. However, treatment with OT attenuated these adverse effects. OT effectively restored the levels of antioxidant enzymes, such as catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD). OT reduced lipid peroxidation, as indicated by decreased malondialdehyde (MDA) levels. OT preserved normal spermatogenesis, improved morphometric parameters, and reduced histological changes by MTX. Moreover, OT effectively restored testosterone levels. CONCLUSIONS: OT protects against MTX-induced testicular damage by suppressing oxidative stress.
Asunto(s)
Metotrexato , Estrés Oxidativo , Ozono , Testículo , Testosterona , Animales , Masculino , Metotrexato/efectos adversos , Metotrexato/toxicidad , Ratones , Testículo/efectos de los fármacos , Testículo/patología , Estrés Oxidativo/efectos de los fármacos , Testosterona/sangre , Peroxidación de Lípido/efectos de los fármacos , Antioxidantes/farmacología , Malondialdehído/metabolismoRESUMEN
5-fluorouracil (5-FU) and methotrexate (MTX) are among the most widely consumed antineoplastic drugs worldwide. These drugs are known as emerging pollutants, once after consumption are excreted by feces and/or urine in a mixture of compounds and metabolites, entering the aquatic environment due to low efficiency in drug removal by effluent treatment plants. Considering that these substances may interact with the DNA, causing metabolic and morphological changes, leading to cell death, the present study aimed to investigate the potential impact of a long-term exposure to these antineoplastic drugs in environmentally relevant concentrations, on testicular morphophysiology of rats. Male Wistar rats (70 days old) were distributed into 4 groups (n = 10 / group): control, received only vehicle; MTX, received methotrexate at 10ngL-1 in drinking water; 5-FU received 5-fluorouracil at 10ngL-1 in drinking water; and MTX+ 5FU, received the combination of MTX and 5-FU at 10ngL-1 each. The treatment period was from postnatal day (PND)70 to PND160, when the animals were euthanized for evaluation of testicular toxicity and changes in endocrine signaling. In these experimental conditions, both drugs acted as endocrine disruptors causing cytotoxic effects in the testes of exposed rats, altering the structural pattern of seminiferous tubules and leading to oxidative stress even at environmental concentrations.
Asunto(s)
Antineoplásicos , Disruptores Endocrinos , Animales , Masculino , Ratas , Antineoplásicos/toxicidad , Agua Potable , Fluorouracilo/toxicidad , Metotrexato/toxicidad , Ratas Wistar , Disruptores Endocrinos/toxicidad , Contaminación Química del AguaRESUMEN
SUMMARY: We aimed to investigate the protective effect of linoleic acid on liver toxicity induced by methotrexate. The study was carried out in partnership with the Department of Anatomy and Department of Medical Pharmacology of Çukurova University Faculty of Medicine, using the laboratory facilities of the Department of Medical Pharmacology. Human hepatocyte cell line (CRL- 11233) cells obtained from the American Type Culture Collection Organization (ATCC) were used. Expressions of apoptotic pathway markers, apoptosis inducing factor (AIF), BAX, BCL 2, GADD 153, 78-kDa glucose-regulated protein (GRP78), and CASPASE-3 were evaluated. All analyzes were examined in four groups (Group 1; control, Group 2; linoleic acid given, Group 3; methotrexate given and Group 4; linoleic acid and methotrexate given). The mean ± standard error values of the obtained results as nanogram / milliliter (ng / ml) are in Group I, Group II, Group III and Group IV, respectively; AIF values, 0.4150 ± 0.1208, 0.3633 ± 0.2389, 1.792 ± 0.3611 and 1.077 ± 0.1646, BAX values, 0.900 ± 0.1864, 1.002 ± 0.2098, 8.352 ± 1.467 and 4.295 ± 1.522, BCL 2 values, 13.93 ± 1.198, 13.92 ± 1.739, 2.938 ± 1.059 and 9.250 ± 1.492, GADD 153, 0.7333 ± 0.1751, 0.7067 ± 0.2115, 1.650 ± 0.2950 and 1.237 ± 0.1805, GRP78, 0.4767 ± 0.1804, 0.5233 ± 0.1590, 2.183 ± 0.2639 and 1.112 ± 0.2693, CASPASE-3 values , 1.127 ± 0.2033, 0.8317 ± 0.3392, 13.50 ± 1.871 and 8.183 ± 1.030. It was determined that linoleic acid has a protective effect on methotrexate-induced liver toxicity.
Nuestro objetivo fue investigar el efecto protector del ácido linoleico sobre la toxicidad hepática inducida por metotrexato. El estudio se llevó a cabo en colaboración con el Departamento de Anatomía y el Departamento de Farmacología Médica de la Facultad de Medicina de la Universidad de Çukurova, utilizando las instalaciones del laboratorio del Departamento de Farmacología Médica. Se usaron células de la línea celular de hepatocitos humanos (CRL-11233) obtenidas de la American Type Culture Collection Organisation (ATCC). Se evaluaron las expresiones de marcadores de vías apoptóticas, factor inductor de apoptosis (AIF), BAX, BCL 2, GADD 153, proteína regulada por glucosa de 78 kDa (GRP78) y CASPASE-3. Todos los análisis se examinaron en cuatro grupos (Grupo 1; control, Grupo 2; se administró ácido linoleico, Grupo 3; se administró metotrexato y Grupo 4; se administró ácido linoleico y metotrexato). Los valores medios ± error estándar de los resultados obtenidos como nanogramo/mililitro (ng/ml) se encuentran en el Grupo I, Grupo II, Grupo III y Grupo IV, respectivamente; Valores de AIF, 0,4150 ± 0,1208, 0,3633 ± 0,2389, 1,792 ± 0,3611 y 1,077 ± 0,1646, valores de Bax, 0,900 ± 0,1864, 1,002 ± 0,2098, 8,352 ± 1,467 y 4,295 ± 1,522, BCL 2 valores, 13,93 ± 1,199. 2,938 ± 1,059 y 9,250 ± 1,492, GADD 153, 0,7333 ± 0,1751, 0,7067 ± 0,2115, 1,650 ± 0,2950 y 1,237 ± 0,1805, Grp78, 0,4767 ± 0,1804, 0,5233 ± 0,1590, 2,183, ± 1,263. 1,127 ± 0,2033, 0,8317 ± 0,3392, 13,50 ± 1,871 y 8,183 ± 1,030. Se determinó que el ácido linoleico tiene un efecto protector sobre la toxicidad hepática inducida por metotrexato.
Asunto(s)
Humanos , Metotrexato/toxicidad , Ácido Linoleico/administración & dosificación , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Ensayo de Inmunoadsorción Enzimática , Células Cultivadas , Sustancias Protectoras , Hepatocitos/efectos de los fármacos , Factor Inductor de la Apoptosis , Caspasa 3 , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Chaperón BiP del Retículo Endoplásmico , Hígado/citología , Hígado/efectos de los fármacos , Antimetabolitos Antineoplásicos/toxicidadRESUMEN
The present study aimed to investigate the beneficial of prepared black rice anthocyanins nano-composite (An-AgNps) against hepatotoxicity induced by methotrexate (MTX) in rats. Anthocyanins nano-composite was prepared by silver as the metallic ion reduction and were characterized by IR and SEM. The rats in our experiment were divided into five groups. Serum lipid profile, serum transaminases (ALT and AST), ALP, LDH, TBA, GSH and SOD were examined. The results show that SEM of An-AgNps has average particle size from 70 to 130nm. In the group treated with MTX; TC, TG, LDL-c, ALT, AST, ALP, LDH and TBA levels were significantly (P≤0.05) increased than NC, while, HDL-c, SOD and GSH levels were significantly (P≤0.05) decreased. On the other hand, An-AgNps + MTX treated groups were reversed the levels of all biomarkers similar to NC. In conclusion, the results show that An-AgNps has a protective effect on MTX-induced hepatotoxicity and oxidative stress.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Oryza , Animales , Antocianinas/farmacología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Metotrexato/toxicidad , Estrés Oxidativo , RatasRESUMEN
A systematic study was carried out to evaluate the uptake and cytotoxicity of methotrexate (MTX) conjugated to superparamagnetic iron oxide nanoparticles (SPIONs) modified with glycerol phosphate (Glyc) and phosphorylethanolamine (PEA), using MCF-7 cancer cell line as model. The ligand shell composition was controlled in such a way to get SPIONs with nine different surface functionalization and up to three co-conjugated ligands but the very iron oxide core, in order to test and compare uptake and cytotoxicity, and verify possible additive effects. Folic acid (FA), the non-toxic analogue of MTX, was also explored as ligand for SPIONs. Glyc was shown to enhance dramatically the cellular uptake despite the high negative zeta potentials, whereas PEA, FA and MTX was found to have a much lower effect on the cellular uptake. Also, a significant ten times lowering of IC50 was observed for the co-conjugated MTX in the SPION-Glyc/PEA/MTX as compared to the free drug, whereas the analogue SPION-Glyc/PEA/FA nanoparticles exhibited no significant cytotoxicity. In short, the conjugation of MTX to SPIONs enhanced dramatically its cytotoxicity and decreased the IC50 value against MCF-7 tumor cells as compared to the free drug, probably due to the enhanced uptake of SPIONs as a result of their surface modification with Glyc/PEA, demonstrating that SPION-Glyc/PEA is a good nanocarrier for co-conjugated methotrexate.
Asunto(s)
Nanopartículas de Magnetita , Metotrexato , Supervivencia Celular , Glicerol , Glicerofosfatos , Humanos , Nanopartículas Magnéticas de Óxido de Hierro , Nanopartículas de Magnetita/toxicidad , Metotrexato/toxicidad , FosfatosAsunto(s)
Humanos , Masculino , Adulto , Sarcoidosis/etiología , Bloqueo Atrioventricular/diagnóstico por imagen , Cardiopatías/complicaciones , Cardiopatías/diagnóstico por imagen , Azatioprina/farmacología , Factores de Tiempo , Ecocardiografía , Espectroscopía de Resonancia Magnética , Metotrexato/toxicidad , Taquicardia Ventricular/complicaciones , Bisoprolol/química , Corticoesteroides/administración & dosificación , Angiografía por Tomografía Computarizada , Insuficiencia Cardíaca/complicaciones , Amiodarona/química , Anticoagulantes/químicaRESUMEN
Methotrexate is used to treat autoimmune and oncologic diseases in children with Down syndrome. However, increased methotrexate-related toxicity is reported in this population. We evaluated differences in the concentrations and distribution of erythrocyte folates in children with Down syndrome as a potential basis for this enhanced toxicity.
Asunto(s)
Síndrome de Down/sangre , Ácido Fólico/sangre , Homeostasis , Preescolar , Eritrocitos/metabolismo , Ácido Fólico/administración & dosificación , Humanos , Metotrexato/farmacología , Metotrexato/toxicidad , Proyectos Piloto , Muestreo , Complejo Vitamínico B/administración & dosificaciónAsunto(s)
Humanos , Servicios Preventivos de Salud , Medicina Clínica , Investigación/educación , Disfunciones Sexuales Fisiológicas/tratamiento farmacológico , Antipsicóticos/efectos adversos , Neoplasias Laríngeas/cirugía , Metotrexato/toxicidad , Atención Dirigida al Paciente/métodos , Cigomicosis/complicaciones , Microbioma Gastrointestinal/genéticaRESUMEN
Abstract Methotrexate (MTX) was shown to cause oxidative stress and liver damage. The objective was to investigate the possible protective effects of Matricaria Chamomilla L. (chamomile) extract with anti-oxidant and anti-inflammatory properties on the methotrexate-induced liver toxicity. Twenty four Wistar rats were divided into four groups. MTX group was injected intraperitoneally on days 7 and 14 with 20 mg/kg methotrexate. Groups CE200 (chamomile extract 200 mg/kg/day) and CE300 (chamomile extract 300 mg/kg/day) received the same dose of methotrexate added with chamomile extract orally for 15 days at 200 mg/kg and 300 mg/kg respectively and the last group was healthy control group. Results of biochemical analyses indicated serum liver biomarkers (aminotransferases), alkaline phosphatase (ALP), albumin, and liver content of anti-oxidant enzymes (catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px)), reduced glutathione (GSH) and total anti-oxidant capacity (TAC) significantly increased (P <0.05-0.001) to normal in the CE treated groups compared to those of the MTX group. Serum bilirubin and hepatic malondialdehyde (MDA) levels significantly increased (P ˂0.001) in MTX group compared to those of the control group and decreased in CE200 and CE300 groups compared to those of the MTX group. Histopathological study showed inflammatory damage, necrotic cells and lipid infiltration in MTX group. In the groups treated with the chamomile extract, a significant improvement was observed in liver tissue in response to increased dose of the extract. In conclusion, chamomile extract administration could have a protective role in methotrexate-induced liver toxicity in rats through improving anti-oxidant defense system.
Asunto(s)
Animales , Masculino , Ratas , Extractos Vegetales/uso terapéutico , Metotrexato/toxicidad , Sustancias Protectoras/uso terapéutico , Matricaria/química , Hígado/efectos de los fármacos , Ratas WistarRESUMEN
Methotrexate (MTX) is a derivate of folic acid, commonly used as an anchor drug for the treatment and management of malignant diseases and autoimmune disorders. However, nephrotoxicity is an important drawback of MTX therapy. Unfortunately, there are not enough studies reporting the nature of the renal failure induced by MTX. Thus, the aim of this study was to evaluate the time course of renal handling of water and electrolytes in male Wistar rats, after the exposure to a unique dose of MTX (80 mg/kg b.w.). Experiments were carried out at day 2, day 4, day 8 and day 14 after MTX administration. Several parameters of kidney function related to water and electrolytes handling were evaluated. Renal expression and urinary excretion of aquaporin-2 (AQP2) and Na-K-2Cl-cotransporter (NKCC2) were determined by Western blotting. MTX produced alterations on water handling on the second day after treatment, showing a significant increase in solute free water reabsorption which might be mediated by the increased expression of AQP2 in apical membranes. On the other hand, MTX produced alterations on electrolytes handling on the fourth day after treatment, showing a significant decrease of sodium chloride excretion, mediated at least in part, by the increase renal expression of NKCC2. These results provide valuable information to clinical practice in order to be able to find therapeutic targets that diminish adverse effects and health deterioration. Moreover, MTX treatment altered AQP2 and NKCC2 urinary excretion allowing postulating these transporters as potential biomarkers of MTX induced nephrotoxicity.
Asunto(s)
Acuaporina 2/metabolismo , Electrólitos/metabolismo , Enfermedades Renales/inducido químicamente , Túbulos Renales/efectos de los fármacos , Metotrexato/toxicidad , Reabsorción Renal/efectos de los fármacos , Miembro 1 de la Familia de Transportadores de Soluto 12/metabolismo , Agua/metabolismo , Animales , Biomarcadores/metabolismo , Cloruros/metabolismo , Enfermedades Renales/metabolismo , Túbulos Renales/metabolismo , Masculino , Potasio/metabolismo , Ratas Wistar , Sodio/metabolismo , Factores de Tiempo , Urodinámica/efectos de los fármacosRESUMEN
Methotrexate drug is commonly used to treat cancer; it is known to cause reproductive damage. Thymoquinone, as a natural component of herbs has many healthy benefits shown in researches. The present study aimed to investigate probable therapeutic effects of Thymoquinone against Methotrexate-induced damage on sperm parameters in mice. In this experimental study, 30 male mice (25-30 g) were divided into five groups of six in each group. The mice were received normal saline (control group), Methotrexate (20 mg/kg), Methotrexate (20 mg/kg) + Thymoquinone (2, 10 and 20 mg/kg) by intraperitoneal injection. On the day after the last injection, the sperm parameters including motility, viability and count of sperms were assessed. Data analysis was performed using one-way ANOVA followed by Tukey test. Methotrexate alone showed a significant reduction in sperm parameters compared to the control group (P=0.00). In groups treated with Methotrexate and Thymoquinone, sperm parameters (motility ,viability, count sperm) did not show any significant differences with control group (P=0.00). Thymoquinone, as a potent antioxidant, could compensate for the toxicity induced by Methotrexate. These medical trends may be useful for diminishing the side effects of Methotrexate on the male reproductive system.
El metotrexato es un fármaco utilizado comúnmente para tratar el cáncer pero además causa daño en los órganos reproductivos. Durante las investigaciones se ha demostrado que la timoquinona, un componente natural de las hierbas, tiene numerosos beneficios. El objetivo del estudio fue investigar el probable efecto terapéutico de la timoquinona contra el daño inducido por metotrexato, en los parámetros espermáticos en ratones. En este estudio experimental, se dividieron 30 ratones machos (25-30 g) en cinco grupos de seis en cada uno. Los ratones recibieron solución salina normal (grupo control), metotrexato (20 mg / kg), metotrexato (20 mg / kg) + timoquinona (2, 10 y 20 mg / kg) por inyección intraperitoneal. El día después de la última inyección, se evaluaron los parámetros espermáticos, incluida la motilidad, la viabilidad y el recuento de espermatozoides. El análisis de los datos se realizó utilizando test de ANOVA seguido de la prueba de Tukey. Durante el uso exclusivo de metotrexato se observó una reducción significativa en los parámetros espermáticos en comparación con el grupo control (P = 0.00). En los grupos tratados con metotrexato y timoquinona, los parámetros espermáticos (motilidad, viabilidad, conteo de espermatozoides) no mostraron diferencias significativas con el grupo control (P = 0.00). Como potente antioxidante, la timoquinona podría compensar la toxicidad inducida por metotrexato. Estas tendencias médicas pueden ser útiles para disminuir los efectos secundarios de metotrexato en el sistema reproductivo masculino.
Asunto(s)
Animales , Masculino , Ratones , Espermatozoides/efectos de los fármacos , Metotrexato/toxicidad , Benzoquinonas/administración & dosificación , Antineoplásicos/toxicidad , Ratones Endogámicos BALB CRESUMEN
O Metotrexato (MTX) é um dos principais fármacos para o tratamento da psoríase. Os efeitos adversos mais importantes são alterações hepáticas e hematológicas. Para tanto foram avaliados as informações registradas em 604 prontuários de portadores de psoríase em um hospital dermatológico da cidade de Bauru. O objetivo do estudo foi avaliar se a interrupção do tratamento com Metrotexato foi decorrentes das alterações laboratoriais das transaminases e exames hematológicos de rotina. A gamaglutamilpeptidase foi a mais alterada entre os pacientes, mas sem correlação significativa entre doses-cumulativas para hepatoxicidade e hematotoxicidade. Assim pode-se cogitar que o metotrexate apresentou um perfil toxicológico semelhante aos dados da literatura o pode justificar seu uso no tratamento da psoríase com aceitável margem de segurança nas doses empregadas para esta doença
Methotrexate (MTX) is one of the main drugs for the treatment of psoriasis. The adverse events have been related to liver, kidney and haematological impairment. Therefore were evaluated 604 medical records of these patients in a dermatological hospital at Bauru. The aim of this study was evaluate if the reason to interruption of therapy with methotrexate was indeed increase of transaminases and impairment haematological tests. The Gamaglutamiltranpeptidadse (-GT) was increased among the patients, however was no correlation between cumulative-doses to liver and haematological toxicity. This way can to say that methotrexate has toxicological profile like in the literature and this fact justify the use this drug in treatment of psoriasis
Asunto(s)
Humanos , Masculino , Femenino , Metotrexato/efectos adversos , Psoriasis/tratamiento farmacológico , Estudios Retrospectivos , Metotrexato/farmacología , Metotrexato/toxicidad , Registros MédicosRESUMEN
Methotrexate (MTX) is widely used in the treatment of some forms of cancer but having severe side effects. The present work aimed to investigate the protective role of propolis treatment against alterations induced by MTX on the hepatic and renal tissues. Rabbits were exposed to MTX (0.25 mg/kg), with or without propolis (50 mg/kg) while hepatic and renal biopsies were examined for histological and histochemical abnormalities. Methotrexate induced hydropic degeneration, pyknosis, sinusoidal dilatation and bile duct hyperplasia in the liver together with renal tubular degeneration, glomerular shrinkage and hyaline droplet precipitation. While propolis partially ameliorated some of the morphometric and biochemical alterations, none of the hepatic alterations induced by MTX was protected by propolis treatment. Nevertheless glomerular shrinkage and renal tubule degeneration were partially protected in animals received both MTX plus propolis. It is concluded that propolis treatment has little or no ameliorative effect in protecting the hepatic and renal tissues from MTX toxicity.
El metotrexato (MTX) es ampliamente utilizado en el tratamiento de algunas formas de cáncer, pero tiene efectos secundarios graves. El presente trabajo tuvo como objetivo investigar el papel protector del tratamiento con própoleo frente a las alteraciones inducidas por el MTX en los tejidos hepático y renal. Se expusieron conejos a MTX (0,25 mg / kg), en grupos con y sin propóleo (50 mg / kg), y se realizaron biopsias hepáticas y renales, que fueron examinadas buscando anomalías histológicas e histoquímicas. El metotrexato indujo la degeneración hidrópica, picnosis, dilatación sinusoidal e hiperplasia del conducto biliar en el hígado, junto con la degeneración tubular renal, la contracción glomerular y la precipitación hialina. Mientras que el propóleo parcialmente mejoró algunas de las alteraciones morfométricas y bioquímicas, ninguna de las alteraciones hepáticas inducidas por MTX fue protegido por el tratamiento con propóleo. Sin embargo, la contracción glomerular y la degeneración de los túbulos renales fueron parcialmente protegidos en animales que recibieron MTX más propóleo. Se concluye que el tratamiento con propóleo tiene poco o ningún efecto mejorador en la protección de los tejidos hepáticos y renales sometidos a la toxicidad de MTX.
Asunto(s)
Animales , Masculino , Conejos , Própolis/administración & dosificación , Metotrexato/toxicidad , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Peso Corporal , Modelos Animales de Enfermedad , Riñón/patología , Hígado/patologíaRESUMEN
PAMAM-grafted TiO2 nanotubes (PAMAM-TiO2NT) have been synthesized and evaluated as new drug nanocarriers, using curcumin (CUR), methotrexate (MTX), and silibinin (SIL) as model therapeutic compounds. TiO2NT were surface-modified using a silane coupling agent and subsequently conjugated with PAMAM dendrimer of the third generation. The characterization of PAMAM-TiO2NT nanomaterials was performed by FTIR, TEM, N2 adsorption-desorption isotherms, XRD, and TGA techniques, which accounted for a 2.6wt.% of PAMAM grafting in the prepared materials. The drug loading capacity, drug release properties, and cytotoxicity of PAMAM-TiO2NT showed a significant improvement compared to pristine TiO2NT, thus revealing the promising properties of these new materials for drug delivery purposes.
Asunto(s)
Dendrímeros/química , Portadores de Fármacos/química , Nanotubos/química , Preparaciones Farmacéuticas/química , Titanio/química , Supervivencia Celular/efectos de los fármacos , Curcumina/química , Curcumina/metabolismo , Curcumina/toxicidad , Liberación de Fármacos , Células HeLa , Humanos , Metotrexato/química , Metotrexato/metabolismo , Metotrexato/toxicidad , Microscopía Electrónica de Transmisión , Preparaciones Farmacéuticas/metabolismo , Silibina , Silimarina/química , Silimarina/metabolismo , Silimarina/toxicidad , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
PURPOSE: To investigate the possible protective effect of rutin on methotrexate induced hepatotoxicity in rats. METHODS: Twenty-two rats were divided into three experimental groups; Control-saline, Mtx, Mtx+Rutin. Hepatic tissue was taken for histological assessment and biochemical assays. Oxidative stress parameters malondialdehyde (MDA), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were investigated. Liver markers aspartate aminotransferase (AST), alanine aminotransferase (ALT) were analyzed in serum. RESULTS: Mtx+Rutin group showed lower histological injury compared to Mtx group, MDA and ALT levels were increased, while SOD and GSH-Px were decreased in Mtx group compared with Control-saline group. MDA and ALT levels were increased, while SOD and GSH-Px were decreased in Mtx group, compared with Mtx +Rutin group. Serum AST levels were similar among the groups. CONCLUSION: Rutin may be a potential adjuvant drug to reduce the hepatic side effects observed during Mtx therapy for various clinical conditions.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Inmunosupresores/toxicidad , Metotrexato/toxicidad , Rutina/uso terapéutico , Alanina Transaminasa/sangre , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Aspartato Aminotransferasas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Femenino , Glutatión Peroxidasa/análisis , Hígado/efectos de los fármacos , Hígado/patología , Malondialdehído/análisis , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Reproducibilidad de los Resultados , Rutina/farmacología , Superóxido Dismutasa/análisisRESUMEN
PURPOSE: To investigate the possible protective effect of rutin on methotrexate induced hepatotoxicity in rats. METHODS: Twenty-two rats were divided into three experimental groups; Control-saline, Mtx, Mtx+Rutin. Hepatic tissue was taken for histological assessment and biochemical assays. Oxidative stress parameters malondialdehyde (MDA), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were investigated. Liver markers aspartate aminotransferase (AST), alanine aminotransferase (ALT) were analyzed in serum. RESULTS: Mtx+Rutin group showed lower histological injury compared to Mtx group, MDA and ALT levels were increased, while SOD and GSH-Px were decreased in Mtx group compared with Control-saline group. MDA and ALT levels were increased, while SOD and GSH-Px were decreased in Mtx group, compared with Mtx +Rutin group. Serum AST levels were similar among the groups. CONCLUSION: Rutin may be a potential adjuvant drug to reduce the hepatic side effects observed during Mtx therapy for various clinical conditions.
Asunto(s)
Animales , Femenino , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Inmunosupresores/toxicidad , Metotrexato/toxicidad , Rutina/uso terapéutico , Alanina Transaminasa/sangre , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Aspartato Aminotransferasas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Glutatión Peroxidasa/análisis , Hígado/efectos de los fármacos , Hígado/patología , Malondialdehído/análisis , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Reproducibilidad de los Resultados , Rutina/farmacología , Superóxido Dismutasa/análisisRESUMEN
PURPOSE: To determine the antioxidant and anti-inflammatory effects of alfa lipoic acid (ALA) on the liver injury induced by methotrexate (MTX) in rats. METHODS: Thirty two rats were randomly assigned into four equal groups; control, ALA, MTX and MTX with ALA groups. Liver injury was performed with a single dose of MTX (20 mg/kg) to groups 3 and 4. The ALA was administered intraperitonealy for five days in groups 2 and 4. The other rats received saline injection. At the sixth day the rats decapitated, blood and liver tissue samples were removed for TNF-α, IL-1ß, malondialdehyde, glutathione, myeloperoxidase and sodium potassium-adenosine triphosphatase levels measurement and histological examination. RESULTS: MTX administration caused a significant decrease in tissue GSH, and tissue Na+, K+ ATPase activity and which was accompanied with significant increases in tissue MDA and MPO activity. Moreover the pro-inflammatory cytokines (TNF-α, IL- ß) were significantly increased in the MTX group. On the other hand, ALA treatment reversed all these biochemical indices as well as histopathological alterations induced by MTX. CONCLUSION: Alfa lipoic acid ameliorates methotrexate induced oxidative damage of liver in rats with its anti-inflammatory and antioxidant effects.
Asunto(s)
Antimetabolitos Antineoplásicos/toxicidad , Antioxidantes/uso terapéutico , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Metotrexato/toxicidad , Ácido Tióctico/uso terapéutico , Animales , Antiinflamatorios/uso terapéutico , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Ensayo de Inmunoadsorción Enzimática , Femenino , Glutatión/análisis , Interleucina-1beta/sangre , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Malondialdehído/análisis , Necrosis/patología , Peroxidasa/análisis , Distribución Aleatoria , Ratas Wistar , Reproducibilidad de los Resultados , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/sangreRESUMEN
PURPOSE: To determine the antioxidant and anti-inflammatory effects of alfa lipoic acid (ALA) on the liver injury induced by methotrexate (MTX) in rats. METHODS: Thirty two rats were randomly assigned into four equal groups; control, ALA, MTX and MTX with ALA groups. Liver injury was performed with a single dose of MTX (20 mg/kg) to groups 3 and 4. The ALA was administered intraperitonealy for five days in groups 2 and 4. The other rats received saline injection. At the sixth day the rats decapitated, blood and liver tissue samples were removed for TNF-α, IL-1β, malondialdehyde, glutathione, myeloperoxidase and sodium potassium-adenosine triphosphatase levels measurement and histological examination. RESULTS: MTX administration caused a significant decrease in tissue GSH, and tissue Na+, K+ ATPase activity and which was accompanied with significant increases in tissue MDA and MPO activity. Moreover the pro-inflammatory cytokines (TNF-α, IL- β) were significantly increased in the MTX group. On the other hand, ALA treatment reversed all these biochemical indices as well as histopathological alterations induced by MTX. CONCLUSION: Alfa lipoic acid ameliorates methotrexate induced oxidative damage of liver in rats with its anti-inflammatory and antioxidant effects. .
Asunto(s)
Animales , Femenino , Masculino , Antimetabolitos Antineoplásicos/toxicidad , Antioxidantes/uso terapéutico , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Metotrexato/toxicidad , Ácido Tióctico/uso terapéutico , Antiinflamatorios/uso terapéutico , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Ensayo de Inmunoadsorción Enzimática , Glutatión/análisis , Interleucina-1beta/sangre , Hígado/efectos de los fármacos , Hígado/patología , Malondialdehído/análisis , Necrosis/patología , Peroxidasa/análisis , Distribución Aleatoria , Ratas Wistar , Reproducibilidad de los Resultados , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/sangreRESUMEN
In this study, the methotrexate (MTX) was incorporated into the poly(e-caprolactone) (PCL) to design implants (MTX PCL implants) aiming the local treatment of inflammatory angiogenesis diseases without causing systemic side effects. Sponges were inserted into the subcutaneous tissue of mice as a framework for fibrovascular tissue growth. After 4days, MTX PCL implants were also introduced, and anti-inflammatory, antiangiogenic, and antifibrogenic activities of the MTX were determined. MTX reduced the vascularization (hemoglobin content), the neutrophil, and monocyte/macrophage infiltration (MPO and NAG activities, respectively), and the collagen deposition in sponges. MTX reduced tumor necrosis factor-a and IL-6 levels, demonstrating its local antiangiogenic and anti-inflammatory effects. Furthermore, hepatotoxicity, nephrotoxicity, and myelotoxicity, which could be induced by the drug, were evaluated. However, MTX did not promote toxicity to these organs, as the levels of AST and ALT (hepatic markers) and creatinine and urea (renal markers) were not increased, and the complete blood count was not decreased. In conclusion, MTX PCL implants demonstrated to be effective in regulating the components of the inflammatory angiogenesis locally established, and presented an acceptable safety profile. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3731-3742, 2015.
Asunto(s)
Inhibidores de la Angiogénesis/administración & dosificación , Antiinflamatorios/administración & dosificación , Metotrexato/administración & dosificación , Poliésteres/química , Acetilglucosaminidasa/metabolismo , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/toxicidad , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/toxicidad , Proliferación Celular , Colágeno/química , Sistemas de Liberación de Medicamentos , Implantes de Medicamentos , Liberación de Fármacos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Interleucina-6/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/patología , Masculino , Metotrexato/farmacología , Metotrexato/toxicidad , Ratones , Ratones Endogámicos BALB C , Neovascularización Patológica/tratamiento farmacológico , Infiltración Neutrófila/efectos de los fármacos , Peroxidasa/metabolismo , Distribución Tisular , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Methotrexate (MTX) is a pro-oxidant compound that depletes dihydrofolate pools and is widely used in the treatment of leukaemia and other malignancies. The efficacy of methotrexate is often limited by mucositis and intestinal injury, which are major causes of morbidity in children and adults. The aim of this study was to evaluate the effect of olmesartan (OLM), an angiotensin II receptor antagonist, on an Intestinal Mucositis Model (IMM) induced by MTX in Wistar rats. IMM was induced via intraperitoneal (i.p.) administration of MTX (7 mg/kg) for three consecutive days. The animals were pre-treated with oral OLM at 0.5, 1 or 5 mg/kg or with vehicle 30 min prior to exposure to MTX. Small intestinal homogenates were assayed for levels of the IL-1ß, IL-10 and TNF-α cytokines, malondialdehyde and myeloperoxidase activity. Additionally, immunohistochemical analyses of MMP-2, MMP-9, COX-2, RANK/RANKL and SOCS-1 and confocal microscopy analysis of SOCS-1 expression were performed. Treatment with MTX + OLM (5 mg/kg) resulted in a reduction of mucosal inflammatory infiltration, ulcerations, vasodilatation and haemorrhagic areas (p<0.05) as well as reduced concentrations of MPO (p<0.001) and the pro-inflammatory cytokines IL-1ß (p<0.001) and TNF-a (p<0.01), and increase anti-inflammatory cytocine IL-10 (p<0.05). Additionally, the combined treatment reduced expression of MMP-2, MMP-9, COX-2, RANK and RANKL(p<0.05) and increased cytoplasmic expression of SOCS-1 (p<0.05). Our findings confirm the involvement of OLM in reducing the inflammatory response through increased immunosuppressive signalling in an IMM. We also suggest that the beneficial effect of olmesartan treatment is specifically exerted during the damage through blocking inflammatory cytocines.