Effect of irbesartan hydrochlorothiazide on endothelial function, hemodynamics and inflammatory response in hypertensive patients

Objective:To observe the effect of irbesartan hydrochloride on endothelial function, hemodynamics and inflammatory response in patients with essential hypertension.Method:A total of 100 patients with essential hypertension admitted from May 2015 to August 2017 in our hospital were divided into observation group (50 cases) and control group (50 cases) according to random number table. The control group was treated with routine treatment, and the observation group was treated with erbesartan hydrochlorothiazide on the basis of routine treatment in the control group. The changes of vascular endothelial function, hemodynamics and inflammatory factors in the two groups were compared.Results: Before treatment, there was no significant difference in vWF, EDD and NMD levels, hemodynamics level and CRP, ICAM-1 and MCP-1 levels. After treatment, the vWF level in the observation group was significantly decreased and the EDD level was significantly increased;while the level of NMD was not significantly changed. After treatment, the level of vWF in the control group was significantly decreased;but there was no significant change in EDD and NMD level. After treatment, vWF level (144.94±16.21)% in the observation group was significantly lower than that in the control group;EDD level (6.81±0.74)% was significantly higher than that in the control group. After treatment, the levels of LBV, HBV and PV in the observation group were significantly lower than those before treatment, while the levels of LBV, HBV and PV in the control group were not significantly different from those before treatment. After treatment, LBV level (13.34±1.41) m.pas, HBV level (5.13±1.34) m.pas and PV level (1.65±0.34) m.pas in the observation group were significantly lower than those in the control group. After treatment, the levels of CRP, ICAM-1 and MCP-1 in both groups were significantly lower than those before treatment. After treatment, the level of CRP (1.71±0.81) mg/L, ICAM-1 level (330.82±68.51) ng/mL and MCP-1 level (3.02±1.06) g/L in the observation group were significantly lower than those in the control group.Conclusion: Irbesartan hydrochlorothiazide treatment of hypertension can play a significant role in the improvement of vascular endothelial function and hemorheology in patients, and can significantly reduce the level of inflammatory response in the body, worthy of clinical application.

Liquid chromatography coupled with mass spectrometry method for the simultaneous quantification of irbesartan and hydrochlorothiazide in human plasma

A simple and sensitive high-performance liquid chromatography mass spectrometry（LC-MS）method for the simultaneous determination of irbesartan and hydrochlorothiazide in human plasma was developed and applied to a pharmacokinetic study. Acetaminophen was used as the internal standard（IS）.Sample pretreatment using liquid-liquid extraction with ethyl acetate was used.The analysis was carried out on an Elite SinoChrom ODS-BP C_（18）column with a mobile phase composed of acetonitrile-water （35：65,v/v）.Target ions were [M-H]^-m/z 427.25 for irbesartan,[M-H]^-m/z 295.95 for hydrochlorothiazide and [M-H]^- m/z 150.05 for the IS via an electrospray ionization（ESI）source.The intra-and inter-day precision（RSD%）was below 14.5% for irbesartan and hydrochlorothiazide,and the accuracy（RE%）was less than 1.9% and-2.0% for irbesartan and hydrochlorothiazide,respectively.The linear calibration curves were obtained in the concentration range of 10-5000 ng/mL （r0.99）for irbesartan and 1-200 ng/mL（r0.99）for hydrochlorothiazide with the lower limit of quantification（LLOQ）of 10 ng/mL and 1 ng/mL,respectively.The method was applied to a clinical pharmacokinetic study of a tablet containing irbesartan and hydrochlorothiazide in healthy Chinese volunteers after oral administration.

Irbesartan对内皮剥脱后血管平滑肌细胞增生的影响

目的：观察新的非肽类血管紧张素Ⅱ的１型（ＡＴ１）受体拮抗剂对血管平滑肌细胞（ＶＳＭＣ）增生的影响。方法：大鼠髂动脉球囊内皮剥脱术后ＶＳＭＣ过度增生模型，采用３Ｈ－ＴｄＲ和３Ｈ－Ｌｅｕ掺入，免疫组化染色检测ＶＳＭＣ中增殖细胞核抗原（ＰＣＮＡ）表达及图象分析血管壁形态学变化的方法。结果：Ｉｒｂｅｓａｒｔａｎ显著减少３Ｈ－ＴｄＲ和３Ｈ－Ｌｅｕ的掺入量，减少新生内膜面积和ＰＣＮＡ阳性细胞数。结论：Ｉｒｂｅｓａｒｔａｎ能抑制大鼠球囊内皮损伤后ＶＳＭＣ增生，可能是防治血管成行术后再狭窄的有效药物。

Irbesartan和培哚普利对压力超负荷大鼠循环与心脏组织RAS的影响

目的 旨在研究血管紧张转换酶 (ACE)抑制剂培哚普利和血管紧张素Ⅱ受体的Ⅰ型受体 (AT1R)拮抗剂Irbesartan对循环和心脏局部组织肾素—血管紧张素系统 (RAS)影响。方法 采用大鼠腹主动脉缩窄模型 ,用放射免疫法测定血浆肾素 (RA)浓度、血管紧张素Ⅱ (AngⅡ )含量 ,心肌RA浓度、AngⅡ含量 ;比色法测血清和心肌ACE活性。结果 循环AngⅡ含量、ACE活性与LVMI之间均无相关性 (r1=0 .0 96 7,r2 =0 .145 0 ,P >0 .0 5 )。Irbestarsan组循环中RA、AngⅡ含量和ACE活性显著高于手术组 (P <0 .0 1) ;培哚普利组循环RA显著高于手术组 (P <0 .0 1) ,ACE活性和AngⅡ含量显著低于手术组 (P <0 .0 1)。手术组心肌AngⅡ含量、ACE活性均与LVMI呈显著正相关 (r1=0 .82 6 6 ,r2 =0 .82 8P <0 .0 1)。Irbesartan组心肌RA、AngⅡ和ACE均显著低于手术组 (P<0 .0 1) ;培哚普利组心肌RA显著高于手术组 (P<0 .0 5 ) ,但ACE活性和AngⅡ含量显著低于手术组 (P<0 .0 1)。结论 心脏局部组织RAS而非循环RAS在压力超负荷致心肌肥大中起重要作用 ,培哚普利和Irbesartan防止心肌肥厚发生的重要机制之一是阻断心脏组织RAS ,抑制心肌组织局部AngⅡ的生成。

Irbesartanf对大鼠髂动脉球囊内皮剥脱后血管壁增殖的影响

目的 观察Ｉｒｂｅｓａｒｔａｎ对血管损伤后内膜增殖的作用。方法２４只髂总动脉球囊内膜剥脱的Ｗｉｓｔａｒ大鼠随机等分为三组，分别于本前１天至术后１４天食管内喂饲Ｉｒｂｅｓａｒｔａｎ ３０ｍｇ／ｋｇ·ｄ或蒸馏水。术后１４天对损伤血管进行形态学检查。结果 Ｉｒｂｅｓａｒｔａｎ显著抑制损伤血管壁中细胞计数增加和内膜增厚以及血管平滑肌细胞增殖，并且有量效关系。对新生内膜中细胞密度影响不大。结论 Ｉｒｂｅｓａｒｔａｎ能够抑制大鼠髂总动脉球囊损伤后内膜增殖，Ｉｒｂｅｓａｒｔａｎ可能是防治血管成形术后再狭窄的有效药物。

Irbesartan对糖尿病大鼠肾组织骨桥蛋白的调节

目的观察血管紧张素Ⅱ(AngⅡ)受体拮抗剂Irbesartan对糖尿病(DM)大鼠肾组织骨桥蛋白(OPN)表达及炎症细胞浸润的影响。方法建立STZ诱导的SD大鼠DM模型,将成模大鼠随机分成模型组、Irbesartan组,同时设正常对照组。各组大鼠采用相应的干预措施处理12w。常规方法检测各组大鼠肾指数、血糖、尿素氮(BUN)、血肌酐(Scr)、尿白蛋白排泄率(UAER);HE染色观察大鼠肾脏病理形态变化;免疫组化法检测肾小管OPN、CD68表达;Western印迹检测OPN在肾皮质的表达。结果模型组大鼠血糖、UAER、BUN、Scr、肾指数显著增高;肾组织OPN、CD68表达明显增多,光镜下肾小管结构异常改变明显,Irbesartan组上述指标明显低于模型组(P<0.01),肾脏超微结构明显改善,但未达到正常对照组水平。结论 Irbesartan可减少DM大鼠肾组织中OPN含量,下调CD68的表达,对肾脏有一定保护作用。

Effect and mechanism of Irbesartan on occurrence of ventricular arrhythmias in rats with myocardial ischemia through connexin43(cx43)

Objective: To explore the effect and mechanism of angiotensin II receptor blockers-Irbesartan on occurrence of ventricular arrhythmias in rats with myocardial ischemia. Methods: Rats with embryonic cardiomyocytes-H9c2 were randomly divided into control group. ischemia group. Irbesartan group and Irbesartan+ischemia group. The cell viability of rats in each group was tested using MTT. Real-time PCR was employed to detect the expression of connexin43 (Cx43) mRNA and western blot to detect the expression of Cx43 and phosphorylated Cx43. SD rats were randomly divided into the sham-operation group (SO). myocardial infarction group (MI). Irbesartan group and MI+ Irbesartan group, with 10 rats in each group. HE staining was employed to observe the change in the pathomorpholouy of left ventricular tissue and TUNEL method to analyze the cell apoptosis in the tissue. The immunofluorescence was adopted to observe the expression and distribution of Cx43 in the left ventricular myocardium and study the change in the expression of Cx43 in the cardiac muscular tissue at mRNA and protein level. Results: The intervention of lrbesartan in the condition of ischemia indicated the significant decrease in the number of necrotic cells. The expression of Cx43 was significantly decreased under the culture of ischemia (P<0.05), but in the presence of Irbesartan, the expression of Cx43 was increased compared with the ischemia group (p<0.01). The results of WB assay showed the similar trend of change at mRNA level. There was the significant difference in the score of ventricular arerythmia between MI group and SO group (P<0.01). The incidence of ventricular tachycardia or ventricular fibrillation was significantly increased compared with the one in SO group (P<0.05). There was the significant difference in the overall score between MI+Irbesartan group and MI group (P<0.05). The expression of Cx43 in the cardiac muscular tissue in MI group was significantly decreased (P<0.01(US) SO group). But the expression of Cx43 was increased after the treatment with Irbesartan. Conclusions: Irbesartan can inhibit the injury of H9c2 cardiomyocytes and the decreased expression of Cx43 that are induced by the ischemic myocardial infarction. Irbesartan can also improve the reconstruction of Cx43 in rats with ischemic myocardium to inhibit the myocardial infarction-induced arrhythmias.

Effects and Mechanism of Irbesartan on Tubulointerstitial fibrosis in 5/6 Nephrectomized Rats

Tubulointerstitial fibrosis(TIF)is a common pathological feature of end-stage kidney disease.Previous studies showed that upregulation of TGFβ1 notably contributed to the chronic renal injury and irbesartan halted the development of TIF in rats with 5/6 renal mass reduction.This study was to investigate the effects of irbesartan on chronic TIF and the mechanism involved TGFβ1 in the rodent model of chronic renal failure involving 5/6 nephrectomy.The results showed that irbesartan significantly attenuated th...

Study on the Pharmacokinetics and Relative Bioavailability of Irbesartan Capsules in Healthy Volunteers

The pharmacokinetics and relative bioavailability were studied in 18 healthy volunteers. A single oral dose of 150 mg irbesartan capsule (test) or tablet (reference) was given to each volunteer according to a randomized 2 way crossover study. The concentrations in plasma were determined by HPLC UV method. The main parameters of irbesartan capsules were: C max : 1.502±0.295 μg/ml, t max : 1.44±0.34 h, t 1/2 : 20.21±14.71 h, AUC 0 t : 11.087±3.443 μg/ml -1 ·h. The relative bioavailability of capsule to tablet was (101.4±28.9) %. The results of statistical analysis showed that two formulations were bioequivalent.

抗高血压药—血管紧张素Ⅱ受体阻断剂依贝沙坦(Irbesartan)

在高血压的发病机制中肾素-血管紧张素系统（RAS）起着重要的作用，血管紧张素转换酶（ACE）抑制剂通过抑制此系统减少了使血管收缩的血管紧张素Ⅱ的产生，但同时又可形成一些病人不能耐受的如咳嗽的药物不良反应。血管紧张素-Ⅱ受体拮抗剂是新一类的降压药，其直接阻滞血管紧张素-Ⅱ的ATI受体，降压作用强，且药物不良反应低，病人耐受性好。本文对此类药物中的新品种依贝沙坦（Irbesaftan）的临床前基础研究、健康志愿者体内进行的药效动力学和药代动力学研究，以及对轻、中度高血压的临床疗效和安全性进行了较全面的综述。

用24小时动态血压监测评价伊贝沙坝(irbesartan)治疗轻、中度原发性高血压的疗效

目的：应用诊室血压（ＣＢＰ）和动态血压监测（ＡＢＰＭ）的方法评价伊贝沙坦（ＩＲＢ）治疗轻中度原发性高血压的降压疗效、谷／峰比率及药物不良反应。方法：采用开放的方法，２３例研究对象经１周药物洗脱期，２周安慰剂期后，服用伊贝沙坦每日一次１５０ｍｇ， ４周末ＳｅＤＢＰ≥ ９０ ｍｍＨｇ者加量至ＩＲＢ每日一次３００ｍｇ，继续服用４周。于安慰剂期末及伊贝沙坦治疗４，８周末测ＣＢＰ、心率并记录体征；于安慰剂期末及治疗８周末各行ＡＢＰＭ和实验室检查一次。ＣＢＰ结果显示８周末总有效率７８％。４，８周末ＳｅＳＢＰ／ＳｅＤＢＰ分别下降（１５．４±１１．５／１０．９±８． ３）和（２２． ３±１０．４／１４．９±１０．４） ｍｍＨｇ。ＡＢＰＭ结果显示 ８周末２４ｈ、日间、夜间血压分别下降（１６．８±６．４／１０．６±４．５）、（１８．１±６．１／１１．８±４．３）、（１０．１±４２．４／７．５±２．６）ｍｍＨｇ。降压Ｔ／Ｐ大于５０％。无咳嗽等药物不良反应。结论：本研究结果表明，伊贝沙坦每日一次１５０～３００ｍｇ为疗效确切、耐受性好的降压药物。

Antioxidative Capacity of Irbesartan

The author investigated the antioxidant effect of irbesartan[2-butyl-3-（{4-[2-（2H-l,2,3,4-tetrazol-5-yl）. phenyl]phenyl}methyl）-1,3-diazaspiro[4.4]non-1-en-4-one], an angiotensin receptor blocker（ARB）, on the oxidation of erythrocytes induced by 2,2-[azobis（2-amidinopropane） hydrochloride]（AAPH） and H2O2 The value of half concentration（IC50） of irbesartan to scavenge radicals was measured by reacting it with 2,2-[azinobis（3-ethylbenzothia- zoline-6-sulfonate） radical eation]（ABTS＋）. Activities of the catalase（CAT）, superoxide dismutase（SOD）, glutathione peroxidase（GSH-Px） and the content of malondialdehyde（MDA） in liver tissue and blood serum of normal-rats were measured by means of speetrophotometry to study the antioxidation function of irbesartan. Results of experiments show that irbesartan can scavenge ABTS＋ and superoxide radicals effectively as well as inhibit AAPH-, H2O2-induced hemolysis of erythrocytes. Irbesartan can also increase the activities of GSH-Px, SOD, CAT and decrease the content of MDA of normal rats. So irbesartan is a good antioxidant.

Irbesartan对冠状动脉粥样硬化小鼠的治疗作用及可能机制

目的:明确Irbesartan对冠状动脉粥样硬化小鼠的治疗作用,并进一步分析可能的机制。方法:将16只雄性Apo E-/-小鼠给予高脂饮食(1.25%胆固醇,10%脂肪)构建冠心病模型。模型建立后将小鼠随机分为治疗组[Irbesartan,50mg/(kg·d),4周]及对照组(等量生理盐水灌胃对照)。采用HE、ELISA、Western blot及免疫荧光技术分析疗效及机制。结果:治疗组小鼠动脉粥样斑块面积显著低于对照组(P<0.05)。治疗组血管内IL-1β、IL-6及TNF-α水平显著低于对照组(P<0.05)。治疗组小鼠血管周围脂肪组织内PPAR-γ及Adiponectin水平显著升高,而Leptin水平显著降低,与对照组相比差异具有统计学意义(P<0.05)。Western blot及免疫荧光证实,Irbesartan显著抑制了治疗组小鼠血管周围脂肪组织内的NF-κB信号通路。结论:Irbesartan通过调节血管周围脂肪组织内PPAR-γ-NF-κb(p65)信号通路,调节血管周围脂肪组织功能及炎症,从而发挥抗动脉粥样硬化疗效。

Pharmacokinetic interaction between irbesartan and Orthosiphon stamineus extract in rat plasma

Orthosiphonstamineus commonly known as kumis kucing has been used traditionally for rheumatoid,gout,renal calculus,hypertension,diabetes,etc.[1].It is often used in combination with synthetic hypertensive drugs like irbesartan.However,both effectiveness combination herbal medicine with modern pharmaceuticals,and the possible adverse effects from herb–drug interactions remain to be verified.

New simple spectrophotometric method for determination of the binary mixtures(atorvastatin calcium and ezetimibe;candesartan cilexetil and hydrochlorothiazide) in tablets

A new simple spectrophotometric method was developed for the determination of binary mixtures without prior separation.The method is based on the generation of ratio spectra of compound X by using a standard spectrum of compound Y as a divisor.The peak to trough amplitudes between two selected wavelengths in the ratio spectra are proportional to concentration of X without interference from Y.The method was demonstrated by determination of two drug combinations.The first consists of the two antihyperlipidemics：atorvastatin calcium（ATV） and ezetimibe（EZE）,and the second comprises the antihypertensives：candesartan cilexetil（CAN） and hydrochlorothiazide（HCT）.For mixture 1,ATV was determined using 10 μg/mL EZE as the divisor to generate the ratio spectra,and the peak to trough amplitudes between 231 and 276 nm were plotted against ATV concentration.Similarly,by using 10 μg/mL ATV as divisor,the peak to trough amplitudes between 231 and 276 nm were found proportional to EZE concentration.Calibration curves were linear in the range 2.5-40 mg/mL for both drugs.For mixture 2,divisor concentration was 7.5 μg/mL for both drugs.CAN was determined using its peak to trough amplitudes at 251 and 277 nm,while HCT was estimated using the amplitudes between 251 and 276 nm.The measured amplitudes were linearly correlated to concentration in the ranges 2.5-50 and 1-30 μg/mL for CAN and HCT,respectively.The proposed spectrophotometric method was validated and successfully applied for the assay of both drug combinations in several laboratory-prepared mixtures and commercial tablets.

Irbesartan desmotropes:Solid-state characterization,thermodynamic study and dissolution properties

Irbesartan (IBS) is a tetrazole derivative and antihypertensive drug that has two interconvertible structures, 1H- and 2H-tautomers. The difference between them lies in the protonation of the tetrazole ring. In the solid-state, both tautomers can be isolated as crystal forms A (1H-tautomer) and B (2H-tautomer). Studies have reported that IBS is a polymorphic system and its forms A and B are related monotropically. These reports indicate form B as the most stable and less soluble form. Therefore, the goal of this contribution is to demonstrate through a complete solid-state characterization, thermodynamic study and dissolution properties that the IBS forms are desmotropes that are not related monotropically. However, the intention is also to call attention to the importance of conducting strict chemical and in solid-state quality controls on the IBS raw materials. Hence, powder X-ray diffraction (PXRD) and Raman spectroscopy (RS) at ambient and non-ambient conditions, differential scanning calorimetry (DSC), hot stage microscopy (HSM), Fourier transform infrared (FT-IR) and scanning electron microscopy (SEM) techniques were applied. Furthermore, intrinsic dissolution rate (IDR) and structural stability studies at 98% relative humidity (RH), 25℃ and 40 ℃ were conducted as well. The results show that in fact, form A is approximately four-fold more soluble than form B. In addition, both IBS forms are stable at ambient conditions. Nevertheless, structural and/or chemical instability was observed in form B at 40℃ and 98% RH. IBS has been confirmed as a desmotropic system rather than a polymorphic one. Consequently, forms A and B are not related monotropically.

<i>Low Dose</i>Irbesartan Has a Renoprotective Effect as High Dose Ramipril in Diabetic Rats Treated with Insulin

Objectives: The aim of this study is to compare the efficacy of the anti-angiotensinic drug, ramipril and irbesartan on the vascular protection of kidneys of streptozotocin (STZ)-induced diabetic rats (DR). Methods: 110 male albino rats were divided into 7 main groups. Group-1 (10 normal control rats;NC). Group-2 (10 rats) was injected intra-peritoneally with STZ (Diabetic Rats;DR). Group-3 (10 DR) is controlled by insulin. Groups 4 to 7 (20 DR), each is subdivided into two subgroups that received either low or high dose of ramipril or irbesartan with or without insulin. Two months post treatment, rat-tail blood was collected to measure: Fasting blood sugar, HbA1c, total serum proteins, albumin and lipid profiles. Urine was collected to measure albuminuria. Kidneys were isolated for histopathological study. Results: Biochemically, both ramipril and irbesartan (without insulin) lowered albumin concentration in urine samples especially at high doses. Histopathologically, there is no beneficial response of both drugs without insulin. Combination of insulin together with either drug has beneficial effects biochemically and histopathologically at high doses. Low dose irbesartan only has renoprotective effect in DR treated with insulin. The other biochemical parameters showed negligible response to both drugs. Conclusion: Low dose irbesartan and high doses of both drugs have renoprotective effect in DR treated with insulin.

Quantitative estimation of irbesartan in two different matrices and its application to human and dog bioavailability studies using LCeMS/MS

A simple,rapid and robust high-throughput assay for the quantitative analysis of irbesartan in plasma from two species using liquid chromatography tandem mass spectrometric method was developed and validated.Solid phase extraction was used and quantification was achieved using a positive electrospray ionization interface under multiple reactions monitoring condition.Complete validation(as per recent regulatory requirements)was done using human plasma.The same method was validated using dog plasma and the validation parameters met respective acceptance criteria.The method has shorter run time of 3 min.This will help in high throughput.The low aliquot volume in the method helped us to take enough sampling time points for better pharmacokinetic profiles.The calibration curve was shown to be linear from 12.1 to 6018.7 ng/ml in human plasma and 12.1 to 5987.2 ng/ml in dog plasma.This method was successfully applied to samples collected during bioavailability studies of irbesartan in humans and dogs.

Validation of Analytical Method of Irbesartan Plasma in Vitro by High Performance Liquid Chromatography-Fluorescence

Irbesartan is an antihypertensive drug whose concentration in blood is very small so it requires a sensitive method of analysis, selective and valid for analysis. In this study, it is carried out optimization of analytical conditions and validation for the analysis of irbesartan in plasma. Chromatography was performed on a C 18 column （250 × 4.6 mm, 5 μm） under isocratic elution with acetonitrile-0.1% formic acid （46：54 v/v）, pH 3.75. Detection was made at excitation 250 nm and emission 370 nm and analyses were run at a flow-rate of 1.0 mL/min at a temperature of 40 ℃. Losartan potassium was used as internal standard. Plasma extraction was done by deproteination with acetonitrile, mixed with vortex for 30 seconds, then centrifuged it at 10,000 rpm for 10 rain. In plasma validation, the recovery was 96.22%, and the lower limit of quantification （LLOQ） in plasma was 2 ng/mL. The method also fulfill the criteria for accuracy and precision intra and inter day by normal values （%Diff） not exceed ± 15%. On the stability study, irbesartan in plasma temperature -20 ℃has been stable for 28 days.