AIM： To evaluate the inhibitive effect of olmesartan to fibroblast proliferation and the anti-scarring effect in Tenon＇s capsule, both in vitro and in vivo.· METHODS： Human primary Tenon＇s capsule fibroblasts...AIM： To evaluate the inhibitive effect of olmesartan to fibroblast proliferation and the anti-scarring effect in Tenon＇s capsule, both in vitro and in vivo.· METHODS： Human primary Tenon＇s capsule fibroblasts were cultured in vitro, treated with up titrating concentrations of olmesartan. The rate of inhibition was tested with methyl thiazol tetrazolium（MTT） method.Real-time PCR was performed to analyze changes in m RNA expressions of the fibrosis-related factors： matrix metalloproteinase-2（MMP-2）, tissue inhibitor of metalloproteinase（TIMP-1,2） and proliferating cell nuclear antigen（PCNA）. Thirty rabbits were divided into5 groups（3, 7, 14, 21, and 28d）. A rabbit conjunctiva flap model was created in each eye. Olmesartan solution was injected subconjunctivally and then evaluated its anti-proliferation and anti-fibrosis effects through the histological morphology and immunohistochemistry of MMP-2 and PCNA in each group. Only the 7d group was treated with Masson＇s trichrome to compare the neovascularization in the subconjunctiva area.·RESULTS： In vitro, cultured Tenon＇s capsule human fibroblasts showed a dose dependent inhibition by olmesartan in MTT. Olmesartan reduced m RNA expressions of MMP-2 and PCNA but increased m RNA expressions of TIMP-1 and TIMP-2. In vivo, the rabbit eyes treated with olmesartan at 3rd, 7th, 14 thand 21stdays demonstrated a significant reduced expressions of MMP-2 and PCNA compared with control eye, no significant difference observed in 28 thday group. The cellular proliferation and neovascularization was suppressed by olmesartan in Masson＇s trichrome observation.·CONCLUSION： By inhibiting fibroblasts in vitro and in vivo, olmesartan prevents the proliferation and activity of fibroblasts in scar tissue formation, which might benefit glaucoma filtering surgery.展开更多
Collagenous sprue(CS) is a pattern of small-bowel injury characterized histologically by marked villous blunting,intraepithelial lymphocytes,and thickened sub-epithelial collagen table. Clinically,patients present wit...Collagenous sprue(CS) is a pattern of small-bowel injury characterized histologically by marked villous blunting,intraepithelial lymphocytes,and thickened sub-epithelial collagen table. Clinically,patients present with diarrhea,abdominal pain,malabsorption,and weight loss. Gluten intolerance is the most common cause of villous blunting in the duodenum; however,in a recent case series by the Mayo Clinic,it has been reported that olmesartan can have a similar effect. In this case report,a 62-year-old female with a history of hypothyroidism and hypertension managed for several years with olmesartan presented with abdominal pain,weight loss,and nausea. Despite compliance to a gluten-free diet,the patient's symptoms worsened,losing 20 pounds in 3 wk. Endoscopy showed thickening,scalloping,and mosaiform changes of the duodenal mucosa. The biopsy showed CS characterized by complete villous atrophy,lymphocytosis,and thickened sub-epithelial collagen table. After 2 mo cessation of olmesartan,the patient's symptoms improved,and follow-up endoscopy was normal with complete villous regeneration. These findings suggest that olmesartan was a contributing factor in the etiology of this patient's CS.Clinicians should be aware of the possibility of druginduced CS and potential reversibility after discontinuation of medication.展开更多
A simple, precise and rapid stability-indicating ultra-performance liquid chromatography (UPLC) method was devel-oped for the simultaneous quantitative determination of Olmesartan, Amlodipine and Hydrochlorothiazide f...A simple, precise and rapid stability-indicating ultra-performance liquid chromatography (UPLC) method was devel-oped for the simultaneous quantitative determination of Olmesartan, Amlodipine and Hydrochlorothiazide from their innovative Pharmaceutical combination drug product, with the presence of degradation products. It involved a 50 mm × 2.1 mm, 1.8 μm Phenyl column. The separation was achieved on simple gradient method. The mobile phase A contains a mixture of sodium perchlorate buffer pH 3.2(0.053M): acetonitrile in the ratio 90:10, v/v, and mobile phase B con- tains a mixture of sodium perchlorate buffer pH 3.2(0.053M): acetonitrile in the ratio 10:90, v/v. The flow rate was 0.7 mL?min–1 and column temperature was maintained at 55?C.The gradient program (T/%B) was set as 0/10, 2/50, 4/80, and 6.0/10. The detector wavelength was 271 nm for Hydrochlorothiazide, 215 for Olmesartan and 237 nm for Amlodipine. The retention times of Olmesartan, Amlodipine, and Hydrochlorothiazide are 3.5, 3.3 and 0.9 minutes;respectively. The total runtime was 6.0 minutes within which three active compounds and their degradation products were separated. The described method was validated with respect to system suitability, specificity, linearity, precision and accuracy. The precision of the assay method was evaluated by carrying out six independent assays of Olmesartan, Amlodipine, and Hydrochlorothiazide (0.004 mg?mL–1, 0.001 mg?mL–1, 0.0025 mg?mL–1). The accuracy of the method was evaluated in triplicate at three concentration levels, i.e. 50%, 100%, and 150% of target test concentration. The described method was linear over the range, 2 to 6 μg?mL–1 for Olmesartan, 0.5 to 1.5 μg?mL–1 Amlodipine and 1.25 to 3.75 μg?mL–1 for Hydrochlorothiazide. The method is fast and is suitable for high-throughput analysis of the drug and one can analyze about 240 samples per working day, facilitating the processing of large-number batch samples.展开更多
The present method provides the detailed description of development and validation of a simple stability indicating re- verse phase column liquid chromatographic method for Olmesartan in the presence of its impurities...The present method provides the detailed description of development and validation of a simple stability indicating re- verse phase column liquid chromatographic method for Olmesartan in the presence of its impurities namely Imp-A, Imp-B, Imp-C, Imp-D, Imp-E, Imp-F and Imp-G and degradation products generated from forced degradation studies. The drug substance was subjected to stress conditions of aqueous hydrolysis, Oxidative, photolytic and thermal stress degradation. The degradation of Olmesartan was observed under acid hydrolysis, base hydrolysis and peroxide. The drug was found to be stable to other stress conditions attempted. Successful separation of the drug from synthetic impu- rities and degradation products formed under stress conditions was achieved on symmetry C18, 150 mm × 4.6 mm, 5μ column using a phosphate buffer, Acetonitrile and Milli Q water. The developed LC method was validated with respect to specificity, linearity, accuracy, precision, raggedness and robustness. The assay method was found to be linear in the range of 250 μg?mL–1 to with 1000 μg?mL–1 correlation coefficient of 0.9999 and the linearity of the impurities was es- tablished from LOQ to 0.4%. Recoveries of assay and impurities were found between 98.5% and 101.2%. The devel- oped LC method to determine the related substances and assay determinations of Olmesartan can be used to evaluate the quality of regular production samples and stability samples. To best of our knowledge, the validated stability indi- cating LC method which separates all the impurities disclosed in this investigation was not published elsewhere.展开更多
Sorafenib was the first multikinase inhibitor to be approved for use in metastatic renal cell carcinoma. Olmesartan medoxomil used in treatment of hypertension and was reported to inhibit angiogenesis in several model...Sorafenib was the first multikinase inhibitor to be approved for use in metastatic renal cell carcinoma. Olmesartan medoxomil used in treatment of hypertension and was reported to inhibit angiogenesis in several models. The present study was designed to assess the safety of a combination of sorafenib plus olmesartan compared to monotherapies in mice bearing Ehrlich’s ascites carcinoma cell line. Mice were divided to seven groups, 1) normal mice, 2) Ehrlich’s ascites carcinoma control, 3 - 5) olmesartan (3, 10, 30 mg/kg/day), respectively, 6) sorafenib (30 mg/kg/day) and 7) the combination group: mice received olmesartan (30 mg/kg/day) plus sorafenib. All drug treatments continued for 21 days. At the end of the experiment, a complete blood count was performed and kidney and liver functions were estimated. The combination therapy produced a non-significant change in most of the measurements of complete blood count and liver enzymes when compared to normal animals. On the other hand, the combined therapy significantly increased blood urea nitrogen when compared to normal group but did not change the serum creatinine level. Concomitant administration of olmesartan with sorafenib did not significantly augment the toxicity of the later. Therefore;olmesartan might be a safe candidate with sorafenib in treatment of cancer if clinical data proved the benefit of this combination.展开更多
Background： Atrial fibrillation （AF） is the rnost frequent tachyarrhythmia in patients with a permanent pacemaker. Angiotensin II receptor antagonists have a protective effect against the occurrence of AF in patien...Background： Atrial fibrillation （AF） is the rnost frequent tachyarrhythmia in patients with a permanent pacemaker. Angiotensin II receptor antagonists have a protective effect against the occurrence of AF in patients with heart diseases. This study aimed to assess the effectiveness of olmcsartan in the prevention of new-onset AF and AF burden in atrioventricular block （AVB） patients with dual-chamber （DDD） pacemaker implantation. Methods： This was a single-center, prospective, randomized, single-blind, controlled clinical study. A total of 116 AVB patients, who received DDD pacemakers implantation with the percentage of ventricular pacing （VP%） _〉40% from April 22, 2011 to December 24, 2012, were prospectively randomized to olrnesartan group （20 mg per day; n - 57） or control group （n = 59）. Patients were lbllowed up using pacernaker prograrnming± 12-lead electrocardiography in the intrinsic sinus rhythm, laboratory examinations, and transthoracic echocardiography at 24 months. Atrial high rate events （AHREs） were defined as 180 beats/min over a minimum of 5 min. AF burden was calculated by the number of hours with AHREs divided by the number of measurement hours. Results： Ten （17.5%） patients in the olmesartan group and 24 patients （40.7%） in the control group occurred new-onset AF, and the difference between two groups was statistically significant （P = 0.04）. AF burden was lower in olmesartan group than that in control group （8.02 ± 3.10% vs. 13.66 ± 6.14%, P = 0.04）. There were no significant differences in mean days to the first occurrence of AHREs and mean cumulative numbers of AHREs between two groups （P = 0.89 and P = 0.42, respectively）. Moreover, olmesartan group had smaller values of maximal P-wave durations and P-wave dispersion （PD） after 24 months follow-up compared with the control group （ 109.5 ± 7.4 ins vs. 113.4 ± 7.1 ms, P = 0.00; and 40.6 ± 4.5 ms vs. 43.3 ± 4.4 ins, P - 0.02, respectively）. Left ventricular end-diastolic diameter and left ventricular qiection traction were not significantly diiTerent between two groups （both P 〉 0.05）. Conclusion： This study suggested that 24-month ofolmesartan therapy could reduce new-onset AF and AF burden in patients with DDD pacemakers.展开更多
Objective: To investigate the neointima formation and the expression of monocyte chemoattractant protein 1 (MCP 1) and tumor necrosis factor α (TNF α) in cuff induced vascular injury in mouse model, and to examine t...Objective: To investigate the neointima formation and the expression of monocyte chemoattractant protein 1 (MCP 1) and tumor necrosis factor α (TNF α) in cuff induced vascular injury in mouse model, and to examine the effect of angiotensin II type 1 receptor (AT 1) blocker, olmesartan, on MCP 1 and TNF α expression and consequently vascular remodeling. Methods: Vascular injury was induced by polyethylene cuff placement around the mouse femoral artery. Some mice were treated with AT 1 receptor blocker, olmesartan, at the dose of 3 mg·kg -1 ·day -1 with an osmotic minipump. Neointima formation and the proliferation of vascular smooth muscle cells (VSMCs) were measured by morphometric analysis and bromodeoxyuridine (BrdU) incorporation. MCP 1 and TNF α expression was detected by Western blot and immunohistochemical staining. Results: We observed neointima formation 14 days after cuff placement as well as VSMCs proliferation in the media and neointima. Cuff placement also induced MCP 1 and TNF α expression in the media and neointima that the VSMCs specifically existed. Treatment of mice with olmesartan at a dose of 3 mg·kg -1 ·day -1 , which did not influence systolic blood pressure, significantly decreased neointima formation and the proliferation of VSMCs. Olmesartan also inhibited MCP 1 and TNF α expression in the injured arteries. Conclusions: Our results demonstrate that blockade of AT 1 receptor inhibits MCP 1 and TNF α expression and thereby improves vascular remodeling.展开更多
基金the Scientific Research and Laboratory Center of the Second Affiliated Hospital of Xi'an Jiaotong University for the technical support
文摘AIM： To evaluate the inhibitive effect of olmesartan to fibroblast proliferation and the anti-scarring effect in Tenon＇s capsule, both in vitro and in vivo.· METHODS： Human primary Tenon＇s capsule fibroblasts were cultured in vitro, treated with up titrating concentrations of olmesartan. The rate of inhibition was tested with methyl thiazol tetrazolium（MTT） method.Real-time PCR was performed to analyze changes in m RNA expressions of the fibrosis-related factors： matrix metalloproteinase-2（MMP-2）, tissue inhibitor of metalloproteinase（TIMP-1,2） and proliferating cell nuclear antigen（PCNA）. Thirty rabbits were divided into5 groups（3, 7, 14, 21, and 28d）. A rabbit conjunctiva flap model was created in each eye. Olmesartan solution was injected subconjunctivally and then evaluated its anti-proliferation and anti-fibrosis effects through the histological morphology and immunohistochemistry of MMP-2 and PCNA in each group. Only the 7d group was treated with Masson＇s trichrome to compare the neovascularization in the subconjunctiva area.·RESULTS： In vitro, cultured Tenon＇s capsule human fibroblasts showed a dose dependent inhibition by olmesartan in MTT. Olmesartan reduced m RNA expressions of MMP-2 and PCNA but increased m RNA expressions of TIMP-1 and TIMP-2. In vivo, the rabbit eyes treated with olmesartan at 3rd, 7th, 14 thand 21stdays demonstrated a significant reduced expressions of MMP-2 and PCNA compared with control eye, no significant difference observed in 28 thday group. The cellular proliferation and neovascularization was suppressed by olmesartan in Masson＇s trichrome observation.·CONCLUSION： By inhibiting fibroblasts in vitro and in vivo, olmesartan prevents the proliferation and activity of fibroblasts in scar tissue formation, which might benefit glaucoma filtering surgery.
文摘Collagenous sprue(CS) is a pattern of small-bowel injury characterized histologically by marked villous blunting,intraepithelial lymphocytes,and thickened sub-epithelial collagen table. Clinically,patients present with diarrhea,abdominal pain,malabsorption,and weight loss. Gluten intolerance is the most common cause of villous blunting in the duodenum; however,in a recent case series by the Mayo Clinic,it has been reported that olmesartan can have a similar effect. In this case report,a 62-year-old female with a history of hypothyroidism and hypertension managed for several years with olmesartan presented with abdominal pain,weight loss,and nausea. Despite compliance to a gluten-free diet,the patient's symptoms worsened,losing 20 pounds in 3 wk. Endoscopy showed thickening,scalloping,and mosaiform changes of the duodenal mucosa. The biopsy showed CS characterized by complete villous atrophy,lymphocytosis,and thickened sub-epithelial collagen table. After 2 mo cessation of olmesartan,the patient's symptoms improved,and follow-up endoscopy was normal with complete villous regeneration. These findings suggest that olmesartan was a contributing factor in the etiology of this patient's CS.Clinicians should be aware of the possibility of druginduced CS and potential reversibility after discontinuation of medication.
文摘A simple, precise and rapid stability-indicating ultra-performance liquid chromatography (UPLC) method was devel-oped for the simultaneous quantitative determination of Olmesartan, Amlodipine and Hydrochlorothiazide from their innovative Pharmaceutical combination drug product, with the presence of degradation products. It involved a 50 mm × 2.1 mm, 1.8 μm Phenyl column. The separation was achieved on simple gradient method. The mobile phase A contains a mixture of sodium perchlorate buffer pH 3.2(0.053M): acetonitrile in the ratio 90:10, v/v, and mobile phase B con- tains a mixture of sodium perchlorate buffer pH 3.2(0.053M): acetonitrile in the ratio 10:90, v/v. The flow rate was 0.7 mL?min–1 and column temperature was maintained at 55?C.The gradient program (T/%B) was set as 0/10, 2/50, 4/80, and 6.0/10. The detector wavelength was 271 nm for Hydrochlorothiazide, 215 for Olmesartan and 237 nm for Amlodipine. The retention times of Olmesartan, Amlodipine, and Hydrochlorothiazide are 3.5, 3.3 and 0.9 minutes;respectively. The total runtime was 6.0 minutes within which three active compounds and their degradation products were separated. The described method was validated with respect to system suitability, specificity, linearity, precision and accuracy. The precision of the assay method was evaluated by carrying out six independent assays of Olmesartan, Amlodipine, and Hydrochlorothiazide (0.004 mg?mL–1, 0.001 mg?mL–1, 0.0025 mg?mL–1). The accuracy of the method was evaluated in triplicate at three concentration levels, i.e. 50%, 100%, and 150% of target test concentration. The described method was linear over the range, 2 to 6 μg?mL–1 for Olmesartan, 0.5 to 1.5 μg?mL–1 Amlodipine and 1.25 to 3.75 μg?mL–1 for Hydrochlorothiazide. The method is fast and is suitable for high-throughput analysis of the drug and one can analyze about 240 samples per working day, facilitating the processing of large-number batch samples.
文摘The present method provides the detailed description of development and validation of a simple stability indicating re- verse phase column liquid chromatographic method for Olmesartan in the presence of its impurities namely Imp-A, Imp-B, Imp-C, Imp-D, Imp-E, Imp-F and Imp-G and degradation products generated from forced degradation studies. The drug substance was subjected to stress conditions of aqueous hydrolysis, Oxidative, photolytic and thermal stress degradation. The degradation of Olmesartan was observed under acid hydrolysis, base hydrolysis and peroxide. The drug was found to be stable to other stress conditions attempted. Successful separation of the drug from synthetic impu- rities and degradation products formed under stress conditions was achieved on symmetry C18, 150 mm × 4.6 mm, 5μ column using a phosphate buffer, Acetonitrile and Milli Q water. The developed LC method was validated with respect to specificity, linearity, accuracy, precision, raggedness and robustness. The assay method was found to be linear in the range of 250 μg?mL–1 to with 1000 μg?mL–1 correlation coefficient of 0.9999 and the linearity of the impurities was es- tablished from LOQ to 0.4%. Recoveries of assay and impurities were found between 98.5% and 101.2%. The devel- oped LC method to determine the related substances and assay determinations of Olmesartan can be used to evaluate the quality of regular production samples and stability samples. To best of our knowledge, the validated stability indi- cating LC method which separates all the impurities disclosed in this investigation was not published elsewhere.
文摘Sorafenib was the first multikinase inhibitor to be approved for use in metastatic renal cell carcinoma. Olmesartan medoxomil used in treatment of hypertension and was reported to inhibit angiogenesis in several models. The present study was designed to assess the safety of a combination of sorafenib plus olmesartan compared to monotherapies in mice bearing Ehrlich’s ascites carcinoma cell line. Mice were divided to seven groups, 1) normal mice, 2) Ehrlich’s ascites carcinoma control, 3 - 5) olmesartan (3, 10, 30 mg/kg/day), respectively, 6) sorafenib (30 mg/kg/day) and 7) the combination group: mice received olmesartan (30 mg/kg/day) plus sorafenib. All drug treatments continued for 21 days. At the end of the experiment, a complete blood count was performed and kidney and liver functions were estimated. The combination therapy produced a non-significant change in most of the measurements of complete blood count and liver enzymes when compared to normal animals. On the other hand, the combined therapy significantly increased blood urea nitrogen when compared to normal group but did not change the serum creatinine level. Concomitant administration of olmesartan with sorafenib did not significantly augment the toxicity of the later. Therefore;olmesartan might be a safe candidate with sorafenib in treatment of cancer if clinical data proved the benefit of this combination.
文摘Background： Atrial fibrillation （AF） is the rnost frequent tachyarrhythmia in patients with a permanent pacemaker. Angiotensin II receptor antagonists have a protective effect against the occurrence of AF in patients with heart diseases. This study aimed to assess the effectiveness of olmcsartan in the prevention of new-onset AF and AF burden in atrioventricular block （AVB） patients with dual-chamber （DDD） pacemaker implantation. Methods： This was a single-center, prospective, randomized, single-blind, controlled clinical study. A total of 116 AVB patients, who received DDD pacemakers implantation with the percentage of ventricular pacing （VP%） _〉40% from April 22, 2011 to December 24, 2012, were prospectively randomized to olrnesartan group （20 mg per day; n - 57） or control group （n = 59）. Patients were lbllowed up using pacernaker prograrnming± 12-lead electrocardiography in the intrinsic sinus rhythm, laboratory examinations, and transthoracic echocardiography at 24 months. Atrial high rate events （AHREs） were defined as 180 beats/min over a minimum of 5 min. AF burden was calculated by the number of hours with AHREs divided by the number of measurement hours. Results： Ten （17.5%） patients in the olmesartan group and 24 patients （40.7%） in the control group occurred new-onset AF, and the difference between two groups was statistically significant （P = 0.04）. AF burden was lower in olmesartan group than that in control group （8.02 ± 3.10% vs. 13.66 ± 6.14%, P = 0.04）. There were no significant differences in mean days to the first occurrence of AHREs and mean cumulative numbers of AHREs between two groups （P = 0.89 and P = 0.42, respectively）. Moreover, olmesartan group had smaller values of maximal P-wave durations and P-wave dispersion （PD） after 24 months follow-up compared with the control group （ 109.5 ± 7.4 ins vs. 113.4 ± 7.1 ms, P = 0.00; and 40.6 ± 4.5 ms vs. 43.3 ± 4.4 ins, P - 0.02, respectively）. Left ventricular end-diastolic diameter and left ventricular qiection traction were not significantly diiTerent between two groups （both P 〉 0.05）. Conclusion： This study suggested that 24-month ofolmesartan therapy could reduce new-onset AF and AF burden in patients with DDD pacemakers.
文摘Objective: To investigate the neointima formation and the expression of monocyte chemoattractant protein 1 (MCP 1) and tumor necrosis factor α (TNF α) in cuff induced vascular injury in mouse model, and to examine the effect of angiotensin II type 1 receptor (AT 1) blocker, olmesartan, on MCP 1 and TNF α expression and consequently vascular remodeling. Methods: Vascular injury was induced by polyethylene cuff placement around the mouse femoral artery. Some mice were treated with AT 1 receptor blocker, olmesartan, at the dose of 3 mg·kg -1 ·day -1 with an osmotic minipump. Neointima formation and the proliferation of vascular smooth muscle cells (VSMCs) were measured by morphometric analysis and bromodeoxyuridine (BrdU) incorporation. MCP 1 and TNF α expression was detected by Western blot and immunohistochemical staining. Results: We observed neointima formation 14 days after cuff placement as well as VSMCs proliferation in the media and neointima. Cuff placement also induced MCP 1 and TNF α expression in the media and neointima that the VSMCs specifically existed. Treatment of mice with olmesartan at a dose of 3 mg·kg -1 ·day -1 , which did not influence systolic blood pressure, significantly decreased neointima formation and the proliferation of VSMCs. Olmesartan also inhibited MCP 1 and TNF α expression in the injured arteries. Conclusions: Our results demonstrate that blockade of AT 1 receptor inhibits MCP 1 and TNF α expression and thereby improves vascular remodeling.
