ABSTRACT
Using an iron overload mouse model, we explored the protective effect of deferasirox (DFX) and N-acetyl-L-cysteine (NAC) on injured bone marrow hematopoietic stem/progenitor cells (HSPC) induced by iron overload. Mice were intraperitoneally injected with 25 mg iron dextran every 3 days for 4 weeks to establish an iron overload (Fe) model. DFX or NAC were co-administered with iron dextran in two groups of mice (Fe+DFX and Fe+NAC), and the function of HSPCs was then examined. Iron overload markedly decreased the number of murine HSPCs in bone marrow. Subsequent colony-forming cell assays showed that iron overload also decreased the colony forming capacity of HSPCs, the effect of which could be reversed by DFX and NAC. The bone marrow hematopoiesis damage caused by iron overload could be alleviated by DFX and NAC.
Subject(s)
Animals , Male , Acetylcysteine/pharmacology , Triazoles/pharmacology , Benzoates/pharmacology , Hematopoietic Stem Cells/drug effects , Iron Chelating Agents/pharmacology , Free Radical Scavengers/pharmacology , Iron Overload/prevention & control , Protective Agents/pharmacology , Reference Values , Time Factors , Reproducibility of Results , Treatment Outcome , Reactive Oxygen Species/analysis , Colony-Forming Units Assay , Disease Models, Animal , Flow Cytometry , Hematopoiesis/drug effects , Mice, Inbred C57BLABSTRACT
BACKGROUND/AIMS: The treatment of chronic myeloid leukemia (CML) has achieved impressive success since the development of the Bcr-Abl tyrosine kinase inhibitor, imatinib mesylate. Nevertheless, resistance to imatinib has been observed, and a substantial number of patients need alternative treatment strategies. METHODS: We have evaluated the effects of deferasirox, an orally active iron chelator, and imatinib on K562 and KU812 human CML cell lines. Imatinib-resistant CML cell lines were created by exposing cells to gradually increasing concentrations of imatinib. RESULTS: Co-treatment of cells with deferasirox and imatinib induced a synergistic dose-dependent inhibition of proliferation of both CML cell lines. Cell cycle analysis showed an accumulation of cells in the subG1 phase. Western blot analysis of apoptotic proteins showed that co-treatment with deferasirox and imatinib induced an increased expression of apoptotic proteins. These tendencies were clearly identified in imatinib-resistant CML cell lines. The results also showed that co-treatment with deferasirox and imatinib reduced the expression of BcrAbl, phosphorylated Bcr-Abl, nuclear factor-kappaB (NF-kappaB) and beta-catenin. CONCLUSIONS: We observed synergistic effects of deferasirox and imatinib on both imatinib-resistant and imatinib-sensitive cell lines. These effects were due to induction of apoptosis and cell cycle arrest by down-regulated expression of NF-kappaB and beta-catenin levels. Based on these results, we suggest that a combination treatment of deferasirox and imatinib could be considered as an alternative treatment option for imatinib-resistant CML.
Subject(s)
Humans , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Apoptosis Regulatory Proteins/metabolism , Benzoates/pharmacology , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm/drug effects , G1 Phase Cell Cycle Checkpoints/drug effects , Imatinib Mesylate/pharmacology , Iron Chelating Agents/pharmacology , K562 Cells , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Protein Kinase Inhibitors/pharmacology , Signal Transduction/drug effects , Triazoles/pharmacologyABSTRACT
The effects of several antihypertensive drugs on bone mineral density (BMD) and micro-architectural changes in ovariectomized (OVX) mice were investigated. Eight-week-old female C57/BL6 mice were used for this study. Three days after ovariectomy, mice were treated intraperitoneally with nifedipine (15 mg/kg), telmisartan (5 mg/kg), enalapril (20 mg/kg), propranolol (1 mg/kg) or hydrochlorothiazide (12.5 mg/kg) for 35 consecutive days. Uterine atrophy of all mice was confirmed to evaluate estrogen deficiency state. BMD and micro-architectural analyses were performed on tibial proximal ends by micro-computed tomography (micro-CT). When OVX mice with uterine atrophy were compared with mice without atrophy, BMD decreased (P < 0.001). There were significant differences in BMD loss between different antihypertensive drugs (P = 0.005). Enalapril and propranolol increased BMD loss in mice with atrophied uteri compared with control mice. By contrast, thiazide increased BMD in mice with uterine atrophy compared with vehicle-treated mice (P = 0.048). Thiazide (P = 0.032) and telmisartan (P = 0.051) reduced bone loss and bone fraction in mice with uterine atrophy compared with the control. Thiazide affects BMD in OVX mice positively. The reduction in bone loss by thiazide and telmisartan suggest that these drugs may benefit menopausal women with hypertension and osteoporosis.
Subject(s)
Animals , Female , Mice , Antihypertensive Agents/pharmacology , Atrophy , Benzimidazoles/pharmacology , Benzoates/pharmacology , Bone Density/drug effects , Enalapril/pharmacology , Mice, Inbred C57BL , Ovariectomy , Propranolol/pharmacology , Thiazides/pharmacology , Tibia/diagnostic imaging , Tomography, X-Ray Computed , Uterus/anatomy & histologyABSTRACT
The effects of several antihypertensive drugs on bone mineral density (BMD) and micro-architectural changes in ovariectomized (OVX) mice were investigated. Eight-week-old female C57/BL6 mice were used for this study. Three days after ovariectomy, mice were treated intraperitoneally with nifedipine (15 mg/kg), telmisartan (5 mg/kg), enalapril (20 mg/kg), propranolol (1 mg/kg) or hydrochlorothiazide (12.5 mg/kg) for 35 consecutive days. Uterine atrophy of all mice was confirmed to evaluate estrogen deficiency state. BMD and micro-architectural analyses were performed on tibial proximal ends by micro-computed tomography (micro-CT). When OVX mice with uterine atrophy were compared with mice without atrophy, BMD decreased (P < 0.001). There were significant differences in BMD loss between different antihypertensive drugs (P = 0.005). Enalapril and propranolol increased BMD loss in mice with atrophied uteri compared with control mice. By contrast, thiazide increased BMD in mice with uterine atrophy compared with vehicle-treated mice (P = 0.048). Thiazide (P = 0.032) and telmisartan (P = 0.051) reduced bone loss and bone fraction in mice with uterine atrophy compared with the control. Thiazide affects BMD in OVX mice positively. The reduction in bone loss by thiazide and telmisartan suggest that these drugs may benefit menopausal women with hypertension and osteoporosis.
Subject(s)
Animals , Female , Mice , Antihypertensive Agents/pharmacology , Atrophy , Benzimidazoles/pharmacology , Benzoates/pharmacology , Bone Density/drug effects , Enalapril/pharmacology , Mice, Inbred C57BL , Ovariectomy , Propranolol/pharmacology , Thiazides/pharmacology , Tibia/diagnostic imaging , Tomography, X-Ray Computed , Uterus/anatomy & histologySubject(s)
Animals , Humans , Adipokines/metabolism , Angiotensin II Type 1 Receptor Blockers/pharmacology , Benzimidazoles/pharmacology , Benzoates/pharmacology , Insulin Resistance , Obesity/metabolism , Insulin Resistance/physiology , Obesity/drug therapy , Resistin/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Angiotensin II (Ang II) plays a crucial role in the pathogenesis of renal diseases. The objective of the present study was to investigate the possible inflammatory effect of Ang II on glomerular endothelial cells and the underlying mechanism. We isolated and characterized primary cultures of rat glomerular endothelial cells (GECs) and observed that Ang II induced the synthesis of monocyte chemoattractant protein-1 (MCP-1) in GECs as demonstrated by Western blot. Ang II stimulation, at concentrations ranging from 0.1 to 10 µm, of rat GECs induced a rapid increase in the generation of reactive oxygen species as indicated by laser fluoroscopy. The level of p47phox protein, an NAD(P)H oxidase subunit, was also increased by Ang II treatment. These effects of Ang II on GECs were all reduced by diphenyleneiodonium (1.0 µm), an NAD(P)H oxidase inhibitor. Ang II stimulation also promoted the activation of nuclear factor-kappa B (NF-κB). Telmisartan (1.0 µm), an AT1 receptor blocker, blocked all the effects of Ang II on rat GECs. These data suggest that the inhibition of NAD(P)H oxidase-dependent NF-κB signaling reduces the increase in MCP-1 production by GECs induced by Ang II. This may provide a mechanistic basis for the benefits of selective AT1 blockade in dealing with chronic renal disease.
Subject(s)
Animals , Rats , Angiotensin II/pharmacology , /biosynthesis , Endothelial Cells/metabolism , Kidney Glomerulus/cytology , NADPH Oxidases/antagonists & inhibitors , NF-kappa B/metabolism , Angiotensin II Type 1 Receptor Blockers/pharmacology , Blotting, Western , Benzimidazoles/pharmacology , Benzoates/pharmacology , /drug effects , Endothelial Cells/drug effects , Enzyme Inhibitors/pharmacology , Inflammation/metabolism , Onium Compounds/pharmacology , Oxidative Stress/physiology , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolismABSTRACT
BACKGROUND: Telmisartan provides effective treatment of hypertension in a broad spectrum of patients. Aims: To evaluate factors affecting the efficacy of telmisartan in daily clinical practice. SETTING AND DESIGN: Prospective practice-based 12-week uncontrolled cohort study. MATERIALS AND METHODS: Consecutive incident/prevalent outpatients with mild to moderate essential hypertension were started on telmisartan 40 mg/day with optional up-titration to 80 mg/day in order to achieve seated systolic (SSBP) and diastolic (SDBP) blood pressure < 140/90 mm Hg. Intent-to-treat (ITT, N=282) and per protocol (PP, N=275) efficacy assessment was based on SSBP/SDBP reduction and delivered doses. RESULTS: SSBP/SDBP decreased (165.2+/-13.1 / 98.3+/-6.7 mm Hg to 137.9+/-13.2 / 82.6+/-7.3 mm Hg), whilst telmisartan was up-titrated in 40.5% of patients during the study. Multivariate (practically identical ITT and PP) analysis indicated poorer response in obese vs. non-obese patients: lesser SDBP reduction (by around 2.2-2.3 mm Hg, P < 0.05) with higher odds of dose up-titration (odds ratio, OR around 1.90, P < 0.05); and better response in: a) patients started on telmisartan monotherapy than when added to a preexisting treatment: greater SSBP/SDBP reduction (by around 4.0 and 3.0 mm Hg, respectively, P < 0.05) with comparable odds of up-titration; b) diabetics vs. non-diabetics: greater SDBP reduction (by around 3.6-3.7 mm Hg, P < 0.05) with comparable odds of up-titration; c) men vs. women: slightly greater SDBP reduction (by around 1.2 mm Hg, 0.05 P < 0.1) with lower odds of up-titration (OR around 0.51, P < 0.05). CONCLUSION: Previous unsuccessful treatment, obesity, diabetes and gender should be considered in order to optimize the use of telmisartan for mild to moderate essential hypertension in daily clinical practice.
Subject(s)
Adult , Aged , Aged, 80 and over , Angiotensin II Type 1 Receptor Blockers/pharmacology , Antihypertensive Agents/pharmacology , Arteries/physiopathology , Benzimidazoles/pharmacology , Benzoates/pharmacology , Blood Pressure/drug effects , Female , Humans , Hypertension/drug therapy , Male , Middle Aged , Multivariate Analysis , Prospective Studies , Risk Factors , Treatment OutcomeABSTRACT
ICL670(deferasirox) is a tridentate oral iron chelator that has shown high efficacy and theraputic safety in preclinical and currently ongoing phase III clinical evaluation. The drug has been just approved by US FDA for use in iron-loading anaemias. It is an ideal once-daily oral chelator, the effective dose of which is between 20 and 40 mg/kg. Iron is chelated & excreted almost exclusively via the feces. This is a major advance in the field of iron chelation.
Subject(s)
Administration, Oral , Benzoates/pharmacology , Humans , Iron Chelating Agents/pharmacology , Models, Structural , Randomized Controlled Trials as Topic , Triazoles/pharmacology , beta-Thalassemia/drug therapyABSTRACT
The present investigation explored the snake venom neutralizing capacity of four chemical compounds (2-hydroxy-4-methoxy benzoic acid, anisic acid, salicylic acid and aspirin) in experimental animals. The venoms of common Indian snakes Viper russellii, Echis carinatus, Naja kaouthia and Ophiophagus hannah were taken to evaluate the lethal, haemorrhagic and defibrinogenation action neutralization. Lethal action of venom was maximum neutralized with 2-hydroxy-4-methoxy benzoic acid and anisic acid, both in in vitro and in vivo studies. Haemorrhagic activity of venom (Viper and Echis) was maximum neutralized with salicylic acid. Viper venom induced defibrination was maximally neutralized with 2-hydroxy-4-methoxy benzoic acid and anisic acid in vitro studies. The exact mechanisms of venom neutralization by the chemical compounds were not established, except for 2-hydroxy-4-methoxy benzoic acid, where the functional groups, methoxy and hydroxy were partly responsible for the neutralization of the lethal effect and haemorrhagic activity.
Subject(s)
Animals , Benzoates/pharmacology , Evaluation Studies as Topic , Male , Mice , Salicylates/pharmacology , Snake Venoms/antagonists & inhibitorsABSTRACT
Hemos realizado el estudio comparativo con tratamiento de Permetrina al 5 por ciento, Hexacloruro Gama Benceno al 1 por ciento y Benzoato de Bencilo al 30 por ciento en 130 pacientes en el Hospital Militar Regional de Arequipa, realizando un estudio de ensayo clínico, prospectivo y longitudinal distribuido en 4 grupos: Grupo 1 - Permetrina con 33 pacientes. Grupo 2 - Hexacloruro de Benceno Gama con 34 pacientes. Grupo 3 - Benzoato de Bencilo con 33 pacientes. Grupo 4 - Blanco con 30 pacientes. Las lesiones y el prurito para Permetrina comienzan a desaparecer a las 24 horas con 27 pacientes haciendo un 81.81 por ciento y desapareciendo a los 7 dias con 32 pacientes haciendo un 96.97 por ciento. Para Hexacloruro Gama Benceno las lesiones y el prurito comenzaron a desaparecer a las 48 horas, con 20 pacientes, haciendo un 58.52 por ciento y desapareciendo a los 7 dias con 30 pacientes haciendo un 88.23 por ciento. Para Benzoato de Bencilo las lesiones y el prurito comenzaron a desaparecer a los 7 dias con 13 pacientes haciendo un 39.39 por ciento y desaparecieron a los 10 dias con 14 pacientes haciendo un 42.42 por ciento. para Permetrina se logró con la primera aplicación de tratamiento con un 96.97 por ciento de curación, necesitando una segunda aplicación de tratamiento en un 3.03 por ciento con lo que se logro el 100 por ciento de curación. Para H.G.B. se logró la remisión de la enfermedad con la primera aplicación del tratamiento en un 88.23 por ciento necesitando una segunda aplicación de tratamiento en un 11.77 por ciento con lo que se logró el 100 por ciento de curación. Para Benzoato de Bencilo con la primera serie de aplicación del tratamiento se logró en un 42.42 por ciento de remisión de lesiones y necesitó una segunda serie de aplicación de tratamiento en un 57.58 por ciento con lo que se logró el 100 por ciento de curación. Hallamos con el diagnóstico clínico 100 por ciento de escabiosis y utilizamos ademas el método de escarificación con hidroxido de sodio al 10 por ciento, se encontro 2 casos positivos (4 por ciento). Solo hubo 3 pacientes (6 por ciento) con complicaciones de eccematización. A un paciente se le excluyó por que no cumplió con el tratamiento; Ilustramos el trabajo con fotografías con los casos mas importantes.
Subject(s)
Humans , Adult , Benzoates , Benzoates/administration & dosage , Benzoates/pharmacology , Hexachlorocyclohexane , Patients/statistics & numerical data , Scabies/diagnosis , Scabies/therapy , Therapeutics/statistics & numerical data , DermatologyABSTRACT
El benzoato de sodio se ha utilizado en el tratamiento de la encefalopatía hepática hiperamonémica con buenos resultados. Con el objeto de investigar si la combinación de benzoato de sodio con un disacárido (lactosa, lactulosa) tiene un efecto aditivo sobre la disminución de amonio plasmático, se estudió el efecto de la combinación de benzoato de sodio con lactulosa en el modelo de anastomosis portocava en la rata, ya que éste es el modelo experimental que produce mayores elevaciones de amonio en sangre. Se utilizaron ratas Wistar de 250-300 g de peso en las que se practicó una anastomosis porto-cava terminolateral. Diez días después de la operación se inició tratamiento experimental por un periodo de siete días, dividiendo a los animales en cuatro grupos: a) solución salina, b) B.S. 500 mg/kg/día, c) lactulosa 4 g/kg/día, d) benzoato de sodio más lactulosa (dosis anotadas). También se incluyeron un grupo de ratas normales y un grupo con operación ficticia como controles. Se tomaron muestras de sangre arterial al final del periodo de estudio y se determinó amonio por el método enzimático. Resultados. El benzoato de sodio y la lactulosa disminuyeron significativamente las concentraciones de amonio plasmático (437ñ50, 433ñ85 ug/dl, respectivamente) en comparación con el grupo control (638 ñ 50 ug/dl, p = 0.05), tal como se esperaba. La combinación de benzoato de sodio con lactulosa produjo una disminución de amonio aún mayor (264 ñ 17 ug/dl, p<0.001), lo cual apoya la existencia de un efecto aditivo entre ambos fármacos. Estos hallazgos parecen reproducirse en la clínica de acuerdo a estudios clínicos preliminares en los que se ha utilizado la combinación de lactosa con benzoato de sodio. Estos resultados sugieren que puede haber un efecto aditivo entre el benzoato de sodio y disacáridos como la lactulosa, lo cual podría aumentar la eficiencia del tratamiento e incluso disminuir la dosis total de medicamentos y aumentar la tolerancia a cada uno de los fármacos. Finalmente, se plantea la posibilidad de emplear otros fármacos derivados del benzoato de sodio
Subject(s)
Animals , Rats , Sodium/therapeutic use , Sodium/pharmacology , Benzoates/therapeutic use , Benzoates/pharmacology , Combined Modality Therapy , Lactulose/therapeutic use , Lactulose/pharmacology , Hepatic Encephalopathy/physiopathology , Hepatic Encephalopathy/therapyABSTRACT
Com o objetivo de estudar as relacoes quantitativas entre a estrutura quimica e a atividade anti-estricnina em uma serie de derivados 2-sulfamoilbenzoatos, foram determinados parametros fisico-quimicos obtidos pelo metodo CNDO/2, alguns dos quais, juntamente com a conectividade molecular, permitiram estabelecer os fatores que influem na atividade farmacologica e o possivel mecanismo de acao ao nivel molecular