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Objective:To study the effect and mechanism of angiotensin type 1 receptor (AGTR1) blocker olmesartan (OMS) on the apoptosis of human Tenon capsule fibroblasts (HTF).Methods:Tenon capsule tissues were obtained from patients during strabismus surgery in the Second Affiliated Hospital of Xi'an Jiaotong University.Primary HTF were cultured by explant culture.Primary cells were identified by vimentin immunofluorescence staining and flow cytometry.The fibrosis model of HTF was established using 10 ng/ml transforming growth factor-β2 (TGF-β2). The cells were divided into normal control group cultured in culture medium, TGF-β2 group in culture medium containing TGF-β2, TGF-β2+ OMS group in culture medium containing TGF-β2 and OMS, and OMS group in culture medium containing OMS, and were cultured for 48 hours.Cell apoptosis was detected by flow cytometry with annexin V/PI staining.The early apoptosis, late apoptosis, and total apoptosis rates were analyzed.The protein expression of procaspase-9, cleaved caspase-9, bax and bcl-2 in the mitochondrial apoptosis pathway was detected by Western blot.The activity of lactate dehydrogenase (LDH) and superoxide dismutase (SOD) was detected by colorimetry.The study protocol was approved by the Ethics Committee of the Second Affiliated Hospital of Xi'an Jiaotong University (No.2019-014).Results:Primary HTF were successfully isolated and cultured.The cultured cells were long spindle-shaped and positive for vimentin.The expression rate of vimentin in the primary cells was greater than 99%.A statistically statistical difference was found in the early apoptosis rate, late apoptosis rate, and total apoptosis rate among the four groups ( F=24.92, 3.96, 41.82; all at P<0.05). The early and total apoptosis rates were significantly higher in TGF-β2+ OMS group than normal control group and TGF-β2 group, and the late apoptosis rate in TGF-β2+ OMS group was significantly higher than that of normal control group (all at P<0.05). There were statistically significant differences in cleaved caspase-9/procaspase-9, bax, and bax/bcl-2 among the four groups ( F=4.40, 7.98, 4.61; all at P<0.05). The bax/bcl-2 expression was significantly increased in TGF-β2+ OMS group in comparison with normal control group, and the expressions of cleaved caspase-9/procaspase-9, bax, and bax/bcl-2 were significantly elevated in TGF-β2+ OMS group compared with TGF-β2 group (all at P<0.05). LDH activity in the normal control group, TGF-β2 group, TGF-β2+ OMS group and OMS group was (783.99±79.97), (913.16±196.86), (2 529.06±240.21), and (2 134.29±138.96) μmol/(min·L), respectively, showing a statistically significant difference ( F=24.95, P<0.05). Compared with normal control group and TGF-β2 group, LDH activity in TGF-β2+ OMS group was increased, and the differences were statistically significant (both at P<0.05). SOD activity in the normal control group, TGF-β2 group, TGF-β2+ OMS group and OMS group was (50.35±0.97), (41.61±4.56), (28.88±3.26), and (37.61±4.83) μmol/(min·L), respectively, showing a statistically significant difference ( F=5.71, P<0.05). SOD activity was reduced in TGF-β2+ OMS group compared with normal control group and TGF-β2 group, reduced in OMS group compared with normal control group, and the differences were statistically significant (all at P<0.05). Conclusions:AGTR1 blocker OMS can promote the apoptosis of HTF effectively.Mitochondrial apoptosis pathway mediated by bax/bcl-2/caspase-9 and oxidative stress pathway are the potential mechanisms that OMS regulates the apoptosis of HTF.
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There are few studies addressing duodenal inflammation. This study was designed to investigate the effects of a recently developed biotechnological product, a nano-formulation of olmesartan medoxomil (OM) - olmesartan medoxomil zeinmersomes (OMZ) - for the treatment of indomethacin-induced duodenitis in rats. Adult male Wistar rats were given indomethacin (10 mg/kg/day) for four weeks. They were divided into a positive control group (PC, untreated) and two groups treated orally with 3 mg/kg per day of OM or OMZ for the last two weeks of the 4-week indomethacin-treatment. At end of the four weeks, blood and duodenum were collected. Duodenal homogenate was used for measurement of levels of myeloperoxidase, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), malondialdehyde, reduced glutathione (GSH), and cleaved caspase-3. Duodenal sections were stained with H&E. Gene expressions of nuclear factor kappa B (NF-κB p65), Bcl-2-associated X protein (Bax), and B-cell lymphoma 2 (Bcl-2) by RT-PCR, and protein expression of survivin by western blot were assessed. Plasma and duodenal olmesartan concentrations were measured by high performance liquid chromatography mass spectrometry. The duodenitis rats showed significantly higher duodenal levels of myeloperoxidase, TNF-α, IL-6, malondialdehyde, and cleaved caspase-3, a significantly lower GSH level, and histopathological alterations. Moreover, they showed upregulated gene expressions of NF-κB p65 and Bax, downregulated gene expression of Bcl-2, decreased Bcl-2/Bax ratio, and lower protein expression of survivin. OMZ was more effective in protecting the duodenum from indomethacin-induced injuries compared to OM due to improved delivery, higher bioavailability, and better anti-inflammatory, antioxidant, and antiapoptotic effects. OMZ could be a better choice for hypertensive patients with non-steroidal anti-inflammatory drugs-induced duodenitis.
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Resumen La diarrea crónica es una patología frecuente con un amplio diagnóstico diferencial. Presentamos el caso de un paciente con diarrea crónica secundaria a enterocolopatía por la toma prolongada de olmesartán. Se trata de una patología infradiagnosticada por desconocimiento de la entidad, pero que debe considerarse en base a la frecuencia de uso del grupo farmacológico. En nuestro caso, la buena evolución clínica tras la retirada del fármaco nos muestra la necesidad de considerarlo como causa directa del cuadro clínico. Un adecuado enfoque terapéutico en estos pacientes nos permitirá evitar pruebas complementarias, costos innecesarios y se traducirá en una mejora diagnóstica y del pronóstico de estos pacientes. (Acta Med Colomb 2022; 47. DOI:https://doi.org/10.36104/amc.2022.2203).
Abstract Chronic diarrhea is a common pathology with a broad differential diagnosis. We present the case of a patient with chronic diarrhea secondary to enteropathy due to prolonged consumption of olmesartan. This is an underdiagnosed pathology due to lack of knowledge regarding this entity, but it should be considered, given the frequency with which this pharmacological group is used. In our case, the favorable clinical progression after withdrawing the medication indicates the need to consider it as the direct cause of the clinical picture. An appropriate therapeutic approach to these patients will allow us to avoid complementary tests and unnecessary costs, and will translate into a better diagnosis and prognosis in these patients. (Acta Med Colomb 2022; 47. DOI:https://doi.org/10.36104/amc.2022.2203).
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Olmesartan,an angiotensin Ⅱ receptor blocker,is a commonly used antihypertensive drug.Several case reports and cohort studies in recent years have described a severe gastrointestinal adverse event with chronic diarrhea,intestinal malabsorption,and weight loss after the administration of olmesartan.In such cases,the patients recovered after discontinuing olmesartan.This adverse effect is called olmesartan-associated enteropathy(OAE).This article reviews the potential pathogenesis and clinical characteristics of OAE,which broadens the disease spectrum for the differential diagnosis of chronic diarrhea and intestinal malabsorption.
Subject(s)
Humans , Angiotensin Receptor Antagonists , Imidazoles , Intestinal Diseases/diagnosis , Tetrazoles/adverse effectsABSTRACT
Objective:To explore the effect of Olmesartan on the antigen presenting function of dendritic cells (DCs) in rats.Methods:Bone marrow-derived dendritic cells of female Lewis rats were obtained. Bone marrow-derived dendritic cells were cultured with Olmesartan (final concentration 10 μmol/L; OLM-DCs) or equal volume of DMSO (Con-DCs). Mean fluorescence intensity (MFI) of the surface costimulatory molecule CD80, CD86 and MHCⅡ on DCs and the levels of IL-10 and TGF-β of DCs were analyzed by flow cytometry. DCs and CD4 +T lymphocytes were cocultured. T lymphocytes proliferation was analyzed by flow cytometry. IFN-γ in the supernatants were determined by ELISA. Results:The expression of MHC Ⅱ on DCs was inhibited by Olmesartan. The level of intracellular IL-10 in DCs was up-regulated by Olmesartan. Compared with Con-DCs, T lymphocytes proliferation and the level of IFN-γ were inhibited by OLM-DCs.Conclusions:Olmesartan could induce tolerogenic DCs in vitro. These tolerogenic DCs could inhibit T lymphocytes proliferation and the production of Th1 cytokine.
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The liquid chromatography mass spectrometry (LC-MS) compatible, stability-indicating, specific, linear, accurate, sensitive with less run-time related impurities reversed phase high-performance liquid chromatography (RP-HPLC) related impurities method has been developed for olmesartan medoxomil (OLM), chlorthalidone (CHLR), and cilnidipine (CIL) drug combinations, and the method has been validated according to ICH and US-FDA guidelines. The chromatographic separation was performed by using Hypersil-BDS Thermo-Scientific, C18 (12.5 cm, 4.6 mm, 5 microns particle size) column. Mobile phase-A was prepared by mixing 3.85 gm ammonium acetate in HPLC water and adjust pH 5.0 by using diluted acetic acid. Acetonitrile was taken as mobile phase-B. Initial mobile phase ratio (55:45 v/v) was adjusted for mobile phase-A: mobile phase-B followed by gradient program. Other chromatographic conditions such as column temperature 25 degrees, flow rate 1.0 mL/minutes with the detection wavelength at 260 nm. The retention time for CHLR impurity A, olmesartan (OL), OLM impurity A, were found about 2.7, 3.3, and 7.2 minutes respectively, with a total run time of 18.0 minutes. The linearity calibration plot was performed and found linear relationship over the concentration range of 1.25 limit of quantitation (LoQ)–18.75 μg/mL, 3.6 LoQ–60.0 μg/mL, 3.6 LoQ– 60.0 μg/mL respectively for CHLR impurity A, OL and OLM impurity A respectively. The limit of detection (LoD) and LoQ were found 0.4 ppm (μg/mL) and 1.2 ppm (μg/mL), 1.2 ppm (μg/mL) and 3.5 ppm (μg/mL), 1.1 ppm (μg/mL) and 3.3 ppm (μg/mL) for CHLR impurity A, OL and OLM impurity A respectively. The accuracy was determined by recovery studies and was found between 90.0–110.0%. The developed analytical method has been validated for LoD-LoQ, specificity, linearity, accuracy, precision, robustness, and ruggedness, which were well within the acceptance limit as per ICH guidelines. All the degradation products generated by stress conditions were found to be well separated from one another (all drug components and impurities). The developed method with shorter runtime was successfully implemented for routine quality control and stability analysis to check the quality of OLM, CHLR, and CIL drug combinations.
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AIM: To investigate the bioequivalence of domestic olmesartan medoxomil tablets and imported olmesartan medoxomil tablets (Benicar) in Chinese healthy subjects in fasting state. METHODS: This is an open, random and two-way crossover clinical trial involved 24 healthy subjects. A single oral dose 20 mg of domestic olmesartan medoxomil tablets (test preparation) and imported olmesartan medoxomil tablets (control preparation) was administrated under the condition of fasting. The plasma concentrations of olmesartan were determined by LC-MS/MS. The pharmacokinetics parameters were calculated and the bioequivalence of two formulations were evaluated by WinNonlin7.0 program. RESULTS:The main pharmacokinetic parameters of the test and control preparation were as follows: Cmax (702.08±149.24) vs.(706.50±127.00) μg/L; tmax 1.98 (1.33-4.00) vs. 1.98 (1.33-3.50) h; AUC0-t (4 516.93±995.07) vs. (4 543.74±818.45) μg•h•L-1; AUC0-∞ (4 578.16±1 005.73) vs. (4 605.70±820.54) μg•h•L-1; t1/2 (8.00±1.07) vs. (7.94±1.30) h, respectively. The 90% confidence limit of test preparation of the logarithmic transformed parameters Cmax, AUC0-t and AUC0-∞ were in 92.33%-105.29%, 91.86%-105.26%, 91.89%-105.16% vs. the reference preparation, respectively.CONCLUSION: The developed and validated method is rapid, sensitive, selective and reliable for the determination of olmesartan in human plasma; the domestic olmesartan medoxomil tablets are bioequivalence to the imported olmesartan medoxomil tablets.
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OBJECTIVE@#To explore the effects of olmesartan on age-associated migration and invasion capacities and microRNA (miRAN) axis in human aortic vascular smooth muscle cells (HA-VSMCs).@*METHODS@#Cultured HA-VSMCs were divided into control group, bleomycin-mediated senescence (BLM) group and bleomycin + olmesartan treatment group. Wound-healing assay and Boyden chambers invasion assay were used to assess the changes in migration and invasion of the cells, gelatin zymography was used to analyze matrix metalloproteinase-2 (MMP-2) activation in the cells. The differentially expressed miRNAs were identified by miRNA microarray assay and validated by quantitative real-time PCR. MiR-3133 inhibitor was used to examine the effects of molecular manipulation of olmesartan on age-associated migration and invasion and MMP-2 activation in the cells.@*RESULTS@#Compared with those of the control group, the percentage of the repopulated cells and the number of cells crossing the basement membrane increased significantly in BLM group [(78.43±12.76)% (42.47±7.22)%, < 0.05; 33.33±5.51 13.00±4.36, < 0.05]. A significant increase of MMP-2 activation was found in BLM group as compared with the control group (1.66 ± 0.27 0.87 ± 0.13, < 0.05). Olmesartan significantly inhibited BLM-induced enhancement of cell migration and invasion and MMP-2 secretion in the cells. MiR-3133 was significantly downregulated in BLM group and upregulated in olmesartan group. Transfection with miR-3133 inhibitor significantly reversed the effects of olmesartan on age-associated migration and invasion of the cells [(85.87±7.39)% (49.77±3.05)%; 34.67±2.31 20.00±4.58, < 0.05] and MMP-2 activation in the cells (1.76±0.19 0.94±0.10, < 0.05).@*CONCLUSIONS@#Olmesartan inhibits the migration and invasion of ageassociated HA-VSMCs probably by upregulating of the miR-3133 axis.
Subject(s)
Humans , Cell Movement , Cell Proliferation , Cells, Cultured , Imidazoles , Matrix Metalloproteinase 2 , MicroRNAs , Genetics , Muscle, Smooth, Vascular , Myocytes, Smooth Muscle , TetrazolesABSTRACT
OBJECTIVE： To establish the method for simultaneous determination of four known related substances （olmesartan，olmesartan ester dimer ，olmesartan ester alkene ，benzothiadiazine impurity ，called impurity A ，B，C，D for short ）in Olmesartan medoxomil hydrochlorothiazide tablets. METHODS ：HPLC-principal component self-control with correction factor were adopted. The determination was performed on YMC-Triart C 8 column with mobile phase A consisted of acetonitrile- 0.015 mol/L potassium dihydrogen phosphate solution （pH adjusted to 2.8 with phosphoric acid ）（70 ∶ 30，V/V），mobile phase B consisted of acetonitrile-0.015 mol/L potassium dihydrogen phosphate solution （pH adjusted to 2.8 with phosphoric acid ）（15 ∶ 85，V/V）at the flow rate of 0.8 mL/min（gradient elution ）. The detection wavelength was set at 265 nm，and column temperature was 25 ℃. The temperature of injector was 4 ℃；the injection volume was 10 μL. RESULTS：The correction factors of impurity A ，B，C，D were 1.42，1.17，0.89，0.92，respectively. The linear range of olmesartan medoxomil ，hydrochlorothiazide and impurity A ，B，C，D were 0.252 7-7.580 0，1.152 1-4.562 9，0.244 0-18.299 0，0.244 7-3.670 8，0.265 2-3.978 3 and 0.149 9-4.497 3 μg/mL（r≥ 0.999 7），respectively. The limits of detection were 0.084 2，0.050 7，0.081 3，0.081 6，0.088 4，0.050 0 μg/mL，respectively. The quantitative limits were 0.252 7，0.152 1，0.244 0，0.244 7，0.265 2 and 0.149 9 μg/mL，respectively. The results of intermediate precision ，stability（24 h）and repeatability tests all met the relevant requirements. The average recovery rates were 104.00％-108.04％，102.00％-104.94％，100.99％-106.89％，92.00％-95.18％，102.00％-105.06％，103.90％-107.00％（n＝3）， respectively. The contents of impurity A ，B and D in 3 batches of Olmesartan medoxomil hydrochlorothiazide tablets were 0.90％ -1.00％ ，0-0.11％ ，0.16％ -0.24％ ，respectively. The impurity C and other impurities were not detected. There is no significant difference between the results measured by the established method and by the external standard method. CONCLUSIONS：The method has been proved to be highly sensitive and reproducible. It can be used to simultaneously determine four known substances in Olmesartan medoxomil hydrochlorothiazide tablets.
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Los Inhibidores de la enzima convertidora de angiotensina II (IECAs) y antagonistas de los receptores de angiotensina II (ARA II) son drogas usadas comúnmente en el manejo de hipertensión arterial, sin embargo, su uso en el embarazo está asociado con toxicidad fetal.1, 2 La acción de la angiotensina II requiere su unión a dos receptores; AT1, involucrado en el control de la tensión arterial y AT2, probablemente encargado del crecimiento fetal. 2 La angiotensina II es esencial en la hemodinamia sistémica y la filtración glomerular fetal y neonatal. La disminución de la perfusión placentaria por efecto hipotensor en el bloqueo del sistema renina angiotensina aldosterona materno puede determinar hipotensión fetal sistémica, disminución de la filtración glomerular, oligoamnios e insuficiencia renal, anormalidades tubulares, hipoplasia craneal y alto riesgo de muerte perinatal. 2 Reportamos el caso de prematuro de 30 semanas con oligohidramnios severo y exposición materna a olmesartan. Al nacimiento presentó dificultad respiratoria; imposibilidad de mantener una adecuada tensión arterial a pesar de los esfuerzos para conseguir mejorar su tono vascular; anuria sin respuesta a diuréticos; alteraciones craneales; alteraciones metabólicas severas con consecuencias fatales. El tratamiento de hipertensión materna con inhibidores de la enzima convertidora de angiotensina II y los antagonistas de los receptores de angiotensina II está asociada con toxicidad fetal por lo que su uso debe ser evitado durante el embarazo.
Angiotensin II converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists (ARBs) are drugs for general use in the management of arterial hypertension, however their use in gestational hypertension is related to the Fetal toxicity. 1, 2 The action of angiotensin II requires its binding to two receptors; AT1, involved in the control of blood pressure and AT2, probably responsible for fetal growth.2 Angiotensin II is essential in systemic hemodynamics and fetal and neonatal glomerular filtration. The decrease in placental perfusion due to hypotensive effect in the blockade of the maternal rennin angiotensin aldosterone system can determine systemic fetal hypotension, decreased glomerular filtration, oligohydramnios and renal insufficiency, tubular abnormalities, cranial hypoplasia and high risk of perinatal death. 2 We report the case of prematurity of 30 weeks with a history of severe oligohydramnios and maternal exposure to olmesartan. At birth the patient presented in particular respiratory distress; inability to maintain adequate blood pressure despite efforts to improve your vascular tone; anuria without response to diuretics; cranial alterations; metabolic alterations with fatal consequences. The treatment of maternal hypertension with inhibitors of the angiotensin II convective enzyme and angiotensin II receptor antagonists is associated with fetal toxicity and should therefore be avoided during pregnancy
Subject(s)
Angiotensin-Converting Enzyme Inhibitors , Oligohydramnios , Premature Birth , Renal Insufficiency , Angiotensin II , Maternal Exposure , Hypertension, Pregnancy-Induced , Fetal Development , Toxicity , HypotensionABSTRACT
Background: Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) are being used as first line agents for the treatment of hypertension in haemodialysis patients as well as in the general population. Serious hyperkalemia is common in patients with end-stage renal disease, and is observed in about 10% of haemodialysis patients. Although many research have been done so far to compare the antihypertensive efficacy of ARBs, but such studies to evaluate the effect on serum urea, creatinine and potassium levels are not so common in North India region.Methods: In this open label, prospective, randomized study, we evaluated the effect on serum urea, creatinine and potassium levels with use of ARB’s (olmesartan or telmisartan) in stage 1 hypertensive patients (JNCVII). 60 patients were randomized in to two groups. The odd numbers will be allotted olmesartan 20 mg (group A) and even numbers to telmisartan 40 mg (group B). Impacts on serum urea, creatinine and potassium levels were evaluated after 12 weeks.Results: Our results indicates that there was no statistically significant alterations in mean serum creatinine, blood urea and in mean serum potassium levels compared to baseline within the two groups as well as when mean of both groups were compared, olmesartan showed a better reduction in blood pressure as compared to telmisartan.Conclusions: Olmesartan showed a better reduction in blood pressure with similar effects in biochemical parameters as telmisartan.
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Objective :To study therapeutic effect of domestic olmesartan medoxomil on early and middle essential hy‐pertension (EH) and its influence on blood pressure variability (BPV).Methods :A total of 148 EH patients treated in our hospital were selected ,randomly and equally divided into domestic olmesartan medoxomil group (received do‐mestic olmesartan medoxomil treatment ) and Japan olmesartan medoxomil group (received olmesartan medoxomil made in Japan) ,and both groups were continuously treated for eight weeks .BPV indexes ,serum levels of 25－hy‐droxyl vitamin D [25 (OH) D] and homocysteine (Hcy) before and after treatment ,and therapeutic effect and in‐cidence of adverse reactions were observed and compared between two groups .Results :Compared with before treat‐ment ,after treatment ,there were significant reductions in BPV indexes (except nighttime SBP standard deviation ) and serum Hcy level [domestic olmesartan medoxomil group :(23.45 ± 2.48) μmol／L vs .(9.89 ± 1.39) μmol／L ,Ja‐pan olmesartan medoxomil group :(23.48 ± 1.50) μmol／L vs.(9. 83 ± 1.36) μmol／L] ,and significant rise in serum 25 (OH) D level [domestic olmesartan medoxomil group : (294. 89 ± 30.16) ng／L vs .(332. 27 ± 33. 76) ng／L ,Ja‐pan olmesartan medoxomil group :(295.73 ± 30.11) ng／L vs.(329. 71 ± 33. 68 ) ng／L ] in two groups , P＝ 0. 001 all ;there were no significant difference in BPV indexes ,serum levels of 25 (OH) D and Hcy ,total effective rate and incidence rate of adverse reactions after treatment between two groups , P＞ 0. 05 all.Conclusion : Domestic olmesartan medoxomil can significantly reduce BPV indexes with significant therapeutic effect and low incidence rate of adverse reactions in early and middle EH patients ,and it＇s no significant difference compared with olmesartan me‐doxomil made in Japan .It is worth application in clinic .
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BACKGROUND/AIMS: Olmesartan, a widely used angiotensin II receptor blocker (ARB), has been linked to sprue-like enteropathy. No cases of olmesartan-associated enteropathy have been reported in Northeast Asia. We investigated the associations between olmesartan and other ARBs and the incidence of enteropathy in Korea. METHODS: Our retrospective cohort study used data from the Korean National Health Insurance Service to identify 108,559 patients (58,186 females) who were initiated on angiotensin converting enzyme inhibitors (ACEis), olmesartan, or other ARBs between January 2005 and December 2012. The incidences of enteropathy were compared among drug groups. Changes in body weight were compared after propensity score matching of patients in the ACEis and olmesartan groups. RESULTS: Among 108,559 patients, 31 patients were diagnosed with enteropathy. The incidences were 0.73, 0.24, and 0.37 per 1,000 persons, in the ACEis, olmesartan, and other ARBs groups, respectively. Adjusted rate ratios for enteropathy were: olmesartan, 0.33 (95% confidential interval [CI], 0.10 to 1.09; p = 0.070) and other ARBs, 0.34 (95% CI, 0.14 to 0.83; p = 0.017) compared to the ACEis group after adjustment for age, sex, income level, and various comorbidities. The post hoc analysis with matched cohorts revealed that the proportion of patients with significant weight loss did not differ between the ACEis and olmesartan groups. CONCLUSIONS: Olmesartan was not associated with intestinal malabsorption or significant body weight loss in the general Korean population. Additional large-scale prospective studies of the relationship between olmesartan and the incidence of enteropathy in the Asian population are needed.
Subject(s)
Humans , Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors , Asia , Asian People , Body Weight , Cohort Studies , Comorbidity , Drug-Related Side Effects and Adverse Reactions , Incidence , Insurance Claim Review , Intestinal Diseases , Korea , National Health Programs , Propensity Score , Prospective Studies , Receptors, Angiotensin , Retrospective Studies , Weight LossABSTRACT
@#The aim of this study was to establish a high performance liquid chromatography-mass spectrometry method for the determination of 5-(4′-(bromomethyl)-［1, 1′-biphenyl］-2-yl)- 1H-tetrazole(BBT1)and 5-(4′-(dibromomethyl)-［1, 1′-biphenyl］-2-yl)-1H-tetrazole(BBT2), which are two genotoxic impurities in olmesartan medoxomil. Chromatographic separation was based on an Agilent Zorbax Eclipse Plus C18(250 mm × 4. 6 mm, 5 μm)column using water(containing 0. 1% formic acid)- acetonitrile as mobile phase in gradient elution mode. Mass spectrometry was operated in positive ion mode. Selective ion monitors were set at m/z 315 for BBT1 and at m/z 395 for BBT2. Good linear correlations were observed in the range of 0. 009 4- 0. 561 0 μg/mL(r=0. 998)with the quantification limit at 9. 35 ng/mL and the detection limit at 3. 12 ng/mL for BBT1, and in the range of 0. 018 2- 0. 547 5 μg/mL(r=0. 999)with the quantification limit at 18. 25 ng/mL and the detection limit at 6. 08 ng/mL for BBT2. Furthermore, the average recoveries of the three spiked concentration level were 96. 5%(n=9, RSD=4. 8%)and 98. 0%(n=9, RSD=5. 1%)for BBT1 and BBT2, respectively. The proposed method is simple, specific and accurate, and quite suitable for the determination of BBT1 and BBT2 in olmesartan medoxomil.
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Olmesartan medoxomil (OLM) is a novel selective angiotensin II receptor blocker USFDA approved drug for the treatment of hypertension. The oral bioavailability of OLM is 26% in healthy humans due to low solubility in water. The aim of the present investigation was to develop a self–microemulsifying drug delivery system (SMEDDS) to enhance the solubility of OLM. The screening study of OLM with different oils, surfactants and co–surfactants was done. Out of study optimized batch was converted in to solid freeze dried powder using 2% w/v mannitol as cryoprotcatant by lyophilization technique. This freeze dried powder shown good flow properties. The in vitro dissolution shown that about 99.28±0.013%of the drug is released within 45 min in freeze dried Solid–SMEDDS, while plain drug showed only 37.88±0.025% and marketed tablet shown only 58.31±0.015 % dissolution at the end of 45 min. The in vitro dissolution studies indicate that formulation of OLM in the form of freeze dried powder enhances the dissolution properties.
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OBJECTIVE:To investigate the effects of olmesartan medoxomil on cardiac function,plasma N-terminal pro-brain natriuretic peptide(NT-proBNP)and serum interleukin-23(IL-23)in patients with chronic heart failure(CHF),and to evaluation its safety. METHODS:A total of 40 CHF patients selected from Lianshui County People's Hospital of Jiangsu Province during Dec. 2014-May 2016 were divided into control group and observation group according to random number table,with 20 cases in each group. Control group was given Enalapril maleate tablets with initial dose of 5 mg,po,qd(increasing gradually after one week,limiting dose of 20 mg/d)+Metoprolol tartrate tablets 25 mg,po,bid+Isosorbide mononitrate tablets 40 mg,po,qd+Furose-mide tablets 20 mg,po,bid. Observation group was additionally given Olmesartan medoxomil tablets 20 mg,po,qd,on the basis of control group. Both groups received treatment for consecutive 8 weeks. Cardiac function indexes [LVEDD,LAD,IVST,LVP-WT,LVEF,early diastolic peak E filling velocity/late diastolic peak A filling velocity(E/A)],plasma NT-proBNP and serum IL-23 levels were observed in 2 groups before and after treatment. The incidence of ADR was recorded. RESULTS:Before treat-ment,there was no statistical significance in cardiac function indexes,plasma NT-proBNP or serum IL-23 levels between 2 groups (P>0.05).After treatment,LVEDD,LAD,plasma NT-proBNP and serum IL-23 levels of 2 groups were decreased significantly, while LVEF and E/A levels were increased significantly;the observation group was significantly better than control group,with sta-tistical significance(P<0.05). There was no statistical significance in IVST or LVPWT levels between 2 groups before and after treatment,and there was no statistical significance in the incidence of ADR between observation group(25.00%)and control group(20.00%)(P>0.05). CONCLUSIONS:Olmesartan medoxomil can decrease the levels of plasma NT-proBNP and serum IL-23 in CHF patients,and improve cardiac function with good safety.
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OBJECTIVE:To investigate the effects of olmesartan medoxomil on cardiac function,plasma N-terminal pro-brain natriuretic peptide(NT-proBNP)and serum interleukin-23(IL-23)in patients with chronic heart failure(CHF),and to evaluation its safety. METHODS:A total of 40 CHF patients selected from Lianshui County People's Hospital of Jiangsu Province during Dec. 2014-May 2016 were divided into control group and observation group according to random number table,with 20 cases in each group. Control group was given Enalapril maleate tablets with initial dose of 5 mg,po,qd(increasing gradually after one week,limiting dose of 20 mg/d)+Metoprolol tartrate tablets 25 mg,po,bid+Isosorbide mononitrate tablets 40 mg,po,qd+Furose-mide tablets 20 mg,po,bid. Observation group was additionally given Olmesartan medoxomil tablets 20 mg,po,qd,on the basis of control group. Both groups received treatment for consecutive 8 weeks. Cardiac function indexes [LVEDD,LAD,IVST,LVP-WT,LVEF,early diastolic peak E filling velocity/late diastolic peak A filling velocity(E/A)],plasma NT-proBNP and serum IL-23 levels were observed in 2 groups before and after treatment. The incidence of ADR was recorded. RESULTS:Before treat-ment,there was no statistical significance in cardiac function indexes,plasma NT-proBNP or serum IL-23 levels between 2 groups (P>0.05).After treatment,LVEDD,LAD,plasma NT-proBNP and serum IL-23 levels of 2 groups were decreased significantly, while LVEF and E/A levels were increased significantly;the observation group was significantly better than control group,with sta-tistical significance(P<0.05). There was no statistical significance in IVST or LVPWT levels between 2 groups before and after treatment,and there was no statistical significance in the incidence of ADR between observation group(25.00%)and control group(20.00%)(P>0.05). CONCLUSIONS:Olmesartan medoxomil can decrease the levels of plasma NT-proBNP and serum IL-23 in CHF patients,and improve cardiac function with good safety.
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Objective To investigate the effect of olmesartan medoxomil on osteoprotegerin and serum inflammatory factor expression in atherosclerosis model rat.Methods From 2015 April in Jiangsu Institute of schistosomiasis control,24 Sprague-Dawley rats were randomly divided into the following three groups:the control group was fed with standard food,the model group was fed with high fat diet based on standard food(normal food +2％ cholesterol +5％ goat fat +0.2％ acid +7×105 IU/(kg·d) Vitamin D3),and the olmesartan group was given 3 mg/(kg·d) olmesartan gavage daily on the basis of high fat diet.On the fourth week of experiment the level of serum high sensitivity C reactive protein and serum lipids include total cholesterol,low density lipoprotein,high density lipoprotein and triglyceride were detected.The structure and changes of aortic pathology was observed.The expression of osteoprotegerinin in aortic was detected by immunohistochemistry staining and Western blot.Results Within the model group,the level of serum lipid and high-sensitivity C reactive protein increased significantly,endometrial thickness,intima-to-media thickness ratio and osteoprotegerin expression in aorta was significantly higher than that of normal group,the difference was statistically significant(P<0.05).The serum high density lipoprotein increased significantly,the level of other serum lipids and high sensitive C reaction protein decreased significantly,endometrial thickness,intima-to-media thickness ratio and osteoprotegerin expression in aorta of the olmesartan treated rats were significantly lower than those of model animals,the difference was statistically significant(P<0.05).Conclusion Olmesartan may suppress the development of atherosclerosis in model rats by decreasing the expression of osteoprotegerin and the level of serum inflammatory cytokines.
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OBJECTIVE:To explore the effects of olmesartan medoxomil on blood pressure variability(BPV)and vascular en-dothelial function of patients with mild and moderate essential hypertension. METHODS:Sixty patients with mild and moderate es-sential hypertension were included in study group,and other 60 healthy volunteers were included in control group. Study group was given olmesartan medoxomil 20 mg orally,qd,for 4 weeks,followed by same dose if their SBP≤140 mmHg and DBP140 mmHg or DBP≥90 mmHg received double dose till 12th weekend. Aver-age blood pressure,BPV,FMD and NMD of study group were measured before and after treatment as well as the changes in se-rum concentrations of NO and ET,and then compared with control group. RESULTS:Compared with before treatment,average blood pressure,BPV and ET level of study groups were decreased significantly after treatment,serum level of NO was increased significantly,while FMD and NMD were improved significantly,with statistical significance (P0.05). There were 3 cases of mild diarrhea and 2 cases of mild dry cough,and they relieved after medication withont speical treatment. CONCLUSIONS:Olmesartan medoxomil can play a good effect on de-creasing blood pressure and is tolerable. It can also improve the vascular endothelial function.
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La diarrea es un efecto secundario habitual a la toma de fármacos, y en algunas ocasiones la enteropatía perdedora de proteínas tipo "sprue like" puede estar detrás de esta patología. El estudio de esta enfermedad puede suponer un desafío importante para el clínico, sobre todo en los casos que cursan con serología negativa para enfermedad celiaca. La atrofia vellositaria duodenal secundaria a la ingesta de micofenolato-mofetil y metotrexate es bien conocida y descrita desde hace tiempo, pero desde la inclusión en la posológica habitual de olmesartán como antihipertensivo de primera elección hemos objetivado un repunte importante de esta entidad. Debido al amplio uso de esta medicación, queremos poner de manifiesto esta enteropatía iatrogénica a través de dos casos clínicos ocurridos en nuestro hospital en 2014.(AU()
Diarrhea is a common side effect of medical treatment. "Sprue like" enteropathy may be behind this pathology. The study of this disease can be an important clinical challenge, especially in those cases with negative serology for celiac disease. Duodenal villous atrophy secondary to the intake of mycophenolate mofetil and methotrexate have been well known and described but since the inclusion of olmesartán as a first-line antihypertensive, we have seen an important rebound of this entity. Due to the wide use of this medication we want to report this iatrogenic effect through two clinical cases that occurred in our hospital in 2014.(AU)