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1.
J Chromatogr A ; 1466: 67-75, 2016 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-27634211

RESUMEN

For the strict quality control of herbs, a comprehensive strategy based on chromatographic profiles and chemometric methods which could reliably select quantitative indices, robustly quantitate multi-markers and systematically compare different chemometric methods was proposed and successfully applied to the quality analysis of P. cuspidatum. Based on the construction of chromatographic profiles by an efficient accelerated solvent extraction (ASE) and reliable high-performance liquid chromatography-ultraviolet (HPLC-UV) methods, different chemometric methods were employed, namely similarity analyses (SA), hierarchical clustering analysis (HCA) and linear discriminant analysis (LDA). The differences in classification of herb samples were studied for the first time. To reasonably determine the quality of herbs and evaluate different chemometric methods, a comprehensive strategy containing three key steps was performed including selection of quantitative indices, development of a reliable quantification method and adoption of an easily calculated and visible parameter. The quantitative method which was acceptable with good linearity with correlation coefficients >0.9995 and satisfactory repeatability (RSD<1.5%), precision (RSD<2.84%), reproducibility (RSD<2.88%), stability (RSD<2.85%) and recoveries (91.5%-105.6%, RSD<2.83%) was applied to quality evaluation of fourteen batches of the P. cuspidatum samples through simultaneous quantitative determination of fifteen marker compounds. The limits of quantitation of fifteen compounds ranged from 1 to 60µg/ml. From the results of the quality evaluation, it was found that the different calculation theories of the chemometric methods resulted in the variation of classifiers of samples: SA classified samples through the mean values and HCA & LDA classified similar objects.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Fallopia japonica/química , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Control de Calidad , Reproducibilidad de los Resultados
2.
Toxicol Appl Pharmacol ; 307: 45-61, 2016 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-27457977

RESUMEN

EPO-018B, a synthetic peptide-based erythropoiesis stimulating agent (ESA), is mainly designed for treatment of anemia caused by chronic renal failure and chemotherapy against cancer. It overcomes the deficiencies of currently approved ESA, including the frequent administration of temperature-sensitive recombinant protein and anti-EPO antibody-mediated pure red cell aplasia (PRCA). This study was designed to evaluate the potential chronic toxicity of EPO-018B. Subcutaneous administration doses were designed as 0, 0.2, 1 and 10mg/kg for six months for 160 rats (20/gender/group) and 0, 0.3, 3 and 20mg/kg for nine months for 32 monkeys (4/gender/group) once every three weeks. The vehicles received the same volume of physiological saline injection. All animals survived to the scheduled necropsies after six weeks (for rats) and fourteen weeks (for monkeys) recovery period, except for the two high-dose female rats and two high-dose male monkeys, which were considered related to the increased RBCs, chronic blood hyperviscosity and chronic cardiac injury. EPO-018B is supposed to be subcutaneously injected once every month and the intended human therapeutic dose is 0.025mg/kg. The study findings at 0.2mg/kg for rats and 0.3mg/kg for monkeys were considered to be the study NOAEL (the no observed adverse effect level), which were more than ten times the intended human therapeutic dose. Higher doses caused adverse effects related to the liver toxicity, cardiotoxicity, appearance of neutralizing antibodies of EPO-018B and the decrease of serum glucose and cholesterol. Most treatment-induced effects were reversible or revealed ongoing recovery upon the discontinuation of treatment. The sequelae occurred in rats and monkeys were considered secondary to exaggerated pharmacology and would less likely occur in the intended patient population. As to the differences between human beings and animals, the safety of EPO-018B need to be further confirmed in the future clinical studies.


Asunto(s)
Eritropoyetina/análogos & derivados , Eritropoyetina/toxicidad , Hematínicos/toxicidad , Animales , Anticuerpos/sangre , Evaluación Preclínica de Medicamentos , Femenino , Hematínicos/inmunología , Pruebas Hematológicas , Macaca fascicularis , Masculino , Ratas Sprague-Dawley
3.
Artículo en Inglés | MEDLINE | ID: mdl-26959038

RESUMEN

The use of smokeless tobacco (ST) is growing rapidly and globally. The consumption of ST is associated with an increased risk for developing chronic diseases, such as diabetes, hypercholesterolemia, and myocardial infarction, and has led to many public health problems. It is very important to access the toxicity of ST. This experiment presents data from 184-day toxicology studies in Sprague-Dawley (SD) rats designed to characterize the chronic effects of a smokeless tobacco extract (STE). The control group and treatment groups were matched for a range of nicotine levels. Animals were given STE by oral gavage with doses of 3.75 (low-dose), 7.50 (mid-dose) and 15.00 (high-dose) mg · nicotine/kg body weight/day for 184 days, followed by 30 days for recovery. Variables evaluated included body weights, feed consumption, clinical observations, clinical and anatomic pathology (including organ weights), and histopathology. Decreased body weights and organ weights (heart, liver and kidney) were found in animals in the mid-dose and high-dose groups. STE also showed moderate and reversible toxicity in esophagus, stomach, liver, kidney and lung.


Asunto(s)
Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Nicotina/toxicidad , Tamaño de los Órganos/efectos de los fármacos , Extractos Vegetales/toxicidad , Tabaco sin Humo/toxicidad , Administración Oral , Animales , China , Femenino , Masculino , Nicotina/sangre , Extractos Vegetales/sangre , Ratas , Ratas Sprague-Dawley
4.
Regul Toxicol Pharmacol ; 69(3): 558-71, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24928566

RESUMEN

CMS-1, mainly composed of imperatorin as its active compound, is a partially purified fraction of a Chinese herbal medicine, Semen Cnidium monnieri. CMS-1 has the potential to be further developed as a new treatment for hypertension. Thus, we studied its toxicity in both Sprague-Dawley rats and beagle dogs. Rats (0-900mg/kg/day) and dogs (0-450mg/kg/day) received CMS-1 orally for 30 consecutive days, followed by a 15-day recovery period. The major target organs of CMS-1 toxicity are the GI (inappetence), liver (hepatocellular necrosis, enzyme elevation), thymus (atrophy), cardiovascular (hypotension), changes in ECG T and P waveforms, elevation of nitrous oxide levels and hematological (RBC parameters disturbances) systems. Most treatment-induced adverse effects were reversible or showed a progressive recovery upon discontinuation of the treatment. The No Observed Adverse Effect Level (NOAEL) was 100mg/kg/day for rats and 50mg/kg/day for dogs. This non-clinical study suggests that clinical monitoring of CMS-1 in patients should focus on the gastrointestinal system, blood tests for liver functions, electrolytes, and blood homeostasis, cardiovascular functions, and immune functions.


Asunto(s)
Antihipertensivos/efectos adversos , Cnidium/efectos adversos , Plantas Medicinales/efectos adversos , Animales , Perros , Femenino , Pruebas Hematológicas/métodos , Masculino , Óxido Nitroso/metabolismo , Nivel sin Efectos Adversos Observados , Órganos en Riesgo , Ratas , Ratas Sprague-Dawley , Seguridad
5.
Food Chem Toxicol ; 60: 252-62, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23911802

RESUMEN

EPO-018B, a synthetic peptide-based erythropoiesis stimulating agent (ESA), is coupled to polyethylene glycol (PEG) and designed to specifically bind and activate the erythropoietin (EPO) receptor to result in production of red blood cells. This study was designed to evaluate the potential subchronic toxicity of EPO-018B for Cynomolgus monkeys and Sprague-Dawley rats both at 0, 0.5, 5 and 50 mg/kg every week for 5 weeks, followed by 6-week recovery for rats and 12-week recovery for monkeys. The No Observed Adverse Effect Level (NOAEL) for rats and monkeys were both considered to be at least 0.5 mg/kg/day, the minimum toxic dose to be 5.0 mg/kg/day and the severe toxic dose to be more than 50.0 mg/kg/day. The toxicological effects included the exaggerated pharmacology and secondary sequelae that resulted from an erythropoiesis-stimulating agent treatment to healthy animals. Most treatment induced effects were reversible or showed ongoing recovery upon discontinuation of treatment. The anticipated patient population for EPO-018B treatment is targeted to be the anemia patients caused by chronic renal failure or chemotherapy against to cancer and is expected to have an ideal clinical application prospect.


Asunto(s)
Hematínicos/farmacología , Péptidos/farmacología , Polietilenglicoles/farmacología , Animales , Presión Sanguínea , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Eritropoyesis/efectos de los fármacos , Femenino , Inyecciones Subcutáneas , Hígado/efectos de los fármacos , Hígado/metabolismo , Macaca fascicularis , Masculino , Nivel sin Efectos Adversos Observados , Tamaño de los Órganos , Péptidos/efectos adversos , Péptidos/farmacocinética , Polietilenglicoles/efectos adversos , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Ratas , Ratas Sprague-Dawley , Bazo/efectos de los fármacos , Bazo/metabolismo , Pruebas de Toxicidad Subcrónica , Urinálisis
6.
J Ethnopharmacol ; 138(1): 76-84, 2011 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-21893185

RESUMEN

AIM OF THE STUDY: The current study was designed to examine the effects and possible mechanisms of dehydrocavidine (DC) on carbon tetrachloride (CCl4)-induced hepatic fibrosis in male Sprague-Dawley (SD) rats. MATERIALS AND METHODS: Hepatic fibrosis was induced in male rats with CCl4 administration for 12 weeks. Liver histopathological study was performed, and the liver function was examined by determining the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and total bilirubin (TBIL) for evaluating the effect of DC on hepatic fibrosis. The possible mechanisms were investigated by measuring hepatic collagen metabolism and oxidative stress level. Furthermore, oligo microarray analysis of 263 genes was performed, and quantitative real-time RT-PCR was used to verify 4 of the abnormally expressed genes (Bcl2, Cyp3a13, IL18 and Rad50). RESULTS: DC treatment significantly inhibited the loss of body weight and the increase of liver weight induced by CCl4. DC also improved the liver function of rats as indicated by decreased serum enzymatic activities of ALT, AST, ALP and TBIL. Histopathological results indicated that DC alleviated liver damage and reduced the formation of fibrous septa. Moreover, DC significantly decreased liver hydroxyproline (Hyp) and increased urine Hyp. It also decreased liver malondialdehyde concentration, increased activities of liver superoxide dismutase, catalase and glutathione peroxidase. Microarray analysis revealed that DC altered the expression of genes related to apoptosis, cytokines and other proteins involved in tissue repair. CONCLUSIONS: Our findings indicate that DC can protect rats from CCl4-induced hepatic fibrosis through reducing oxidative stress, promoting collagenolysis, and regulating fibrosis-related genes.


Asunto(s)
Antioxidantes/uso terapéutico , Alcaloides de Berberina/uso terapéutico , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Corydalis/química , Cirrosis Hepática/tratamiento farmacológico , Fitoterapia , Extractos Vegetales/uso terapéutico , Animales , Antioxidantes/metabolismo , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Alcaloides de Berberina/farmacología , Tetracloruro de Carbono , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Citocinas/genética , Citocinas/metabolismo , Expresión Génica/efectos de los fármacos , Hidroxiprolina/metabolismo , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/patología , Cirrosis Hepática/etiología , Masculino , Malondialdehído/metabolismo , Análisis por Micromatrices , Extractos Vegetales/farmacología , Ratas , Ratas Sprague-Dawley , Pérdida de Peso/efectos de los fármacos
7.
Regul Toxicol Pharmacol ; 61(2): 230-5, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21856364

RESUMEN

The recombinant soluble human TRAIL mutant (DATR), derived from tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), is a promising agent for cancer therapy. The present study evaluated the toxicity of DATR in rats and monkeys. Based on the results, the safety and toxic doses of DATR intravenously injected to rats for 50 days were 60 and 180 mg/kg, respectively, and when delivered intravenously guttae to monkeys for 50 days, these levels were 10 and 30 mg/kg, respectively. The main toxic effects in rats were red blood cell count and haemoglobin decreases; blood urea nitrogen and creatinine increases. The main toxic effects in monkeys included red blood cell count and haemoglobin decreases; alanine aminotransferase and aspartate aminotransferase increases; high proliferation of karyocytes of the erythrocyte series; and regional hydropic degeneration of hepatic parenchymal cells. The TUNEL assay showed both 90 mg/kg DATR- and TRAIL-induced apoptosis of the liver in monkeys, which confirmed the hepatotoxicity of DATR. These findings indicated that the target toxic organs of DATR might be the haematological system. Furthermore, kidney in rats and liver in monkeys are also likely target toxic organs. The toxicity was reversible and did not differ from that associated with TRAIL administered at the same dosage.


Asunto(s)
Ligando Inductor de Apoptosis Relacionado con TNF/toxicidad , Animales , Evaluación Preclínica de Medicamentos/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Macaca fascicularis , Masculino , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/toxicidad
8.
J Ethnopharmacol ; 117(2): 300-8, 2008 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-18358653

RESUMEN

AIM OF THE STUDY: To investigate the protective effects of dehydrocavidine (DC), a main active ingredient of Corydalis saxicola Bunting (Yanhuanglian), on carbon tetrachloride (CCl4)-induced hepatotoxicity and the possible mechanisms involved in male Sprague-Dawley rats. MATERIALS AND METHODS: Acute hepatotoxicity was induced by CCl4 intoxication in rats. Serum biological analysis, lipid peroxides and antioxidants estimation, histopathological studies were carried out. RESULTS: Both pre-treatment with DC prior to CCl4 administration and post-treatment with DC after CCl4 administration significantly prevented increases in serum enzymatic activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), alkaline phosphatase (ALP) and total bilirubin (TBIL). In addition, pre- and post-treatment with DC also significantly prevented formation of hepatic malondialdehyde (MDA), depletion of glutathione peroxidase (GPx) and depression of superoxide dismutase (SOD) in the liver of CCl4-intoxicated rats. ALT, AST, LDH, ALP and TBILL levels, as well as MDA, SOD and GPx activities were unaffected in normal rats by treatment with DC alone. GST, a phase II enzyme, had no significant changes during our experiments. Histopathological changes induced by CCl4 were also significantly attenuated by DC treatment in both preventive and curative experiments. CONCLUSIONS: DC has a potent hepatoprotective effect on CCl4-induced liver injury in rats through its antioxidant activity.


Asunto(s)
Alcaloides de Berberina/farmacología , Intoxicación por Tetracloruro de Carbono/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Animales , Antioxidantes/farmacología , Cristalización , Glutatión/metabolismo , Glutatión Transferasa/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/metabolismo , Pruebas de Función Hepática , Masculino , Extractos Vegetales/química , Extractos Vegetales/farmacología , Ratas , Ratas Sprague-Dawley , Superóxido Dismutasa/metabolismo
9.
Regul Toxicol Pharmacol ; 50(1): 75-86, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18039554

RESUMEN

The subchronic toxicity and toxicokinetics of a novel proton pump inhibitor, pymeprazole (LZB), were investigated in beagle dogs by daily oral administration for 13 consecutive weeks. Three test groups received doses of 30, 100 and 300 mg/kg/day of LZB. Rabeprazole of 60 mg/kg/day was used as positive control. The 13-week repeated oral doses of LZB resulted in objective signs of mild gastrointestinal disturbance for high-dose group animals. One individual dog of high-dose group was found to be lethargy and astasia at the last month of administration; for hematology, mild anemia was observed at high-dose females; for clinical chemistry, higher cholest, trigly and gastrin were observed at high-dose females, higher ASAT, ALAT, cholesterol, triglyceride and gastrin at high-dose males were also observed; for histopathology, the primary effects of LZB were related to gastric mucosa of high-dose group seen by H and E or Grimelius stain. Impairment of surface epithelium was observed by SEM. The treat-related effects basically were reversible for a 4-week drug-free period. As for positive control group, 13-week oral administration of rabeprazole resulted in more severe toxicity than high-dose group of LZB although much lower dose was employed. The accumulation of LZB after 13-week oral administration was not notable at the toxic dose of 300 mg/kg/day. The toxic dose was considered to be 100mg/kg/day and the no-observed-adverse-effect level (NOAEL) to be 30 mg/kg/day, which is much higher than other PPIs. The toxicological target could be stomach, liver, hematological system and nervous system.


Asunto(s)
Inhibidores de la Bomba de Protones/farmacocinética , Inhibidores de la Bomba de Protones/toxicidad , Piridinas/farmacocinética , Piridinas/toxicidad , Acetilcolinesterasa/sangre , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Colesterol/sangre , Perros , Femenino , Gastrinas/sangre , Pruebas Hematológicas , Riñón/efectos de los fármacos , Riñón/patología , Hígado/efectos de los fármacos , Hígado/patología , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Inhibidores de la Bomba de Protones/sangre , Estómago/efectos de los fármacos , Estómago/patología , Pruebas de Toxicidad , Triglicéridos/sangre
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