Design of Chronomodulated Drug Delivery System of Valsartan: In Vitro Characterization

The aim of the present study was to design and evaluate a chronomodulated time-clock pulsatile tablets of valsartan to release it after a certain lag time, independent of the gastrointestinal pH, in its absorption window to cope with the circadian rhythm of human body for blood pressure elevation. Core tablets were prepared by direct compression of a homogenous mixture of valsartan, Avicel PH101, croscarmellose sodium, magnesium stearate and Aerosil. The core tablets were then sprayed coated with a sealing layer formed of ethyl cellulose that was subsequently coated with a release-controlling layer. Three different aqueous dispersions namely; carnauba wax or beeswax or a mixture in a ratio of 2.5:1, respectively, were used to form five time-clock tablet formulations having the release controlling layer with different thickness {B5, B10, B20, BW5 and CW5}. Quality control testing were carried out to the core tablets. Differential scanning calorimetry was also performed to detect the possible drug excipient interaction in the core tablet formulation. The release was carried out, for the prepared time-clock tablet formulations, in 0.1 N hydrochloric acid for the first 2 h, followed by phosphate buffer (pH 6.8) for 4.5 h. The effect of pH on valsartan release was studied through a release study in 0.1 N hydrochloric acid for 6.5 h. Two phase dissolution study was performed to the selected time-clock tablet formulation to predict the drug permeation through the gastrointestinal tract. Stability study of the selected formula was performed at 25°/60% RH and at 40°/75% RH for 3 months. Results showed that a release-controlling layer composed of a mixture of carnauba wax and beeswax in a ratio of 2.5:1 showed a reasonable release lag time. The release lag time of the tablets increased with the increase of the coat thickness, thus B20>B10>B5 with corresponding lag time values of 4.5, 3 and 2.5 h, respectively. Selected B5 tablet formula exhibited a reasonable lag time after which the highest, complete % drug release at pH 6.8 was obtained. In addition, a good partitioning of valsartan, between the aqueous and organic phases in a ratio of 1:7, was observed. The selected formula was stable for at least 3 months under standard long-term and accelerated storage conditions. In conclusion, in vitro studies revealed that the novel time-clock system could be used successfully to deliver valsartan in a pulsatile pH-independent manner. It provided a desirable lag time followed by a rapid and complete drug release accompanied by an expected effective permeation through the biological membranes upon release in the duodenum; the window of absorption, as indicated by the two phase release study.     

沙库巴曲缬沙坦片对维持性血液透析患者慢性心力衰竭的疗效

目的 观察沙库巴曲缬沙坦片治疗维持性血液透析患者合并慢性心力衰竭的疗效。方法 回顾性分析2019年1月至2020年6月麻城市人民医院肾内科收治的70例维持性血液透析合并慢性心力衰竭患者,将其分为对照组和治疗组,每组各35例,比较两组患者6 min步行试验(6MWT)、左室收缩末期内径(LVESD)、左室舒张末期内径(LVEDD)、左室射血分数(LVEF)、NT-proBNP、cTnT、cTnI、hs-CRP、K+指标的变化。结果 ①治疗组6 MWT较对照组距离延长[(386.72±68.48)min vs.(339.59±69.39)min],差异有统计学意义(P0.05)。②治疗组LVESD和LVEDD较对照组降低[(43.25±5.23)mm、(47.85±9.69)mm vs.(47.89±7.15)mm、(50.52±9.78)mm],差异有统计学意义(P0.05);治疗组LVEF较对照组明显升高[(48.99±4.16)%vs.(40.73±3.75)%],差异有统计学意义(P0.05)。③治疗组NT-proBNP、c TnT、cTnI、hs-CRP较对照组均显著降低,差异有统计学意义(P0.05)。④治疗组与对照组K+比较,差异无统计学意义(P0.05)。结论 沙库巴曲缬沙坦片对维持性血液透析合并慢性心力衰竭患者心室重构有明显改善作用,疗效安全可靠。     

The benefits of valsartan in the treatment of heart failure: results from Val-HeFT

Angiotensin II receptor blockers (ARBs) are the most recent class of anti-hypertensive drug to enter clinical use for chronic heart failure (CHF). In the landmark Valsartan Heart Failure Trial (Val-HeFT), valsartan reduced the risk of the combined endpoint of all-cause mortality and morbidity by 13.2% over a 2-year follow-up. Although it significantly improved a pre-specified primary endpoint, it did not improve the endpoint of all-cause mortality. Valsartan administered to patients not receiving angiotensin-converting enzyme inhibitors (ACEI) at baseline reduced the endpoint of all-cause mortality by 33% and the combined endpoint of mortality and morbidity by 44%, compared with placebo. Based on these findings, valsartan became the first ARB to be approved by the US Food and Drug Administration for the treatment of New York Heart Association class II-IV HF in patients who are intolerant of ACEIs. This review provides a summary of the key Val-HeFT results and their implications in the treatment of CHF patients.     

黄葵胶囊联合缬沙坦治疗早期糖尿病肾病的临床疗效及安全性观察

[目的]观察早期糖尿病肾病患者口服黄葵胶囊联合缬沙坦胶囊治疗的临床疗效及药物安全性。[方法]选取早期糖尿病肾病患者80例,并随机分为观察组与对照组,每组40例。两组患者均给与常规基础治疗,观察组患者给与口服黄葵胶囊联合缬沙坦胶囊进行治疗,对照组患者给与缬沙坦胶囊进行治疗,连续用药疗程均为3个月。比较两组患者治疗前后尿微量白蛋白排泄率(UAER)、血清尿素氮(BUN)及肌酐(Scr)的变化等,进行对比分析。[结果]观察组治疗前后UAER、Scr、BUN比较,差异有统计学意义;对照组治疗前后UAER、BUN、Scr比较,差异有统计学意义。观察组治疗后UAER较对照组降低更为明显(P0.05),两组治疗后BUN和Scr下降程度差异不明显(P0.05)。[结论]使用黄葵胶囊联合缬沙坦胶囊治疗早期糖尿病肾病,两者具有较好的协同作用。     

沙库巴曲缬沙坦治疗急性失代偿射血分数降低心力衰竭患者的有效性和安全性

探讨沙库巴曲缬沙坦（S/V）治疗射血分数降低急性失代偿心力衰竭（ADHF）患者的有效性和安全性。方法 连续纳入2018年5月～2019年10月重庆4个研究中心心血管内科射血分数降低的ADHF患者,根据临床处方信息患者被分为S/V组和血管紧张素转换酶抑制剂（ACEI）/血管紧张素受体阻滞剂（ARB）组（ACEI/ARB组）。住院期间和出院后医生根据患者的一般情况和血压滴定药物剂量,随访至出院后12个月。主要有效性终点是心源性死亡和心衰（HF）住院发生率,次要有效性终点是全因死亡和全因住院发生率。安全性终点肾功能损伤、高钾血症、咳嗽、血管神经性水肿和症状性低血压发生率。结果 筛选期共纳入758例,根据入排标准排除127例,631例纳入倾向性评分,最后502例患者纳入数据分析,S/V组和ACEI/ARB组各251例。S/V组和ACEI/ARB组患者主要疗效性终点心血管死亡和HF住院发生率分别为235%和32.3%（HR:0.687; 95% CI:0.493～0.958; P=0.027）,其中心血管死亡发生率分别为48%和10.4%（HR:0.444; 95% CI: 0.235～0.840; P=0.017）,HF再住院发生率分别为18.7%和21.9%（HR:0.845; 95% CI:0.573～1.247; P=0.398）;次要疗效终点全因死亡和全因住院发生率分别为35.1%和38.2%（HR:0.891; 95% CI:0.668～1.191; P=0.4.37）,其中全因死亡发生率分别为4.8%和11.6%（HR:0.396; 95% CI:0.214～0.731; P=00005）,全因住院发生率分别为30.3%和26.7%（HR, 1.168; 95% CI:0.841～1.622; P=0.352）。安全性终点两组无显著差异。结论 与ACEI/ARB相比,S/V治疗可降低射血分数降低的ADHF患者1年心源性死亡和心衰住院复合终点,并且其安全性相当。     

沙库巴曲缬沙坦治疗急性心肌梗死PCI术后合并慢性心力衰竭的临床效果

目的 探讨沙库巴曲缬沙坦应用于急性心肌梗死经皮冠状动脉介入(PCI)后合并心力衰竭中的临床效果。方法 前瞻性选取内蒙古民族大学第二临床医学院心内科2020年1—6月收治的60例急性心肌梗死PCI术后合并慢性心力衰竭患者作为研究对象;采用数字双盲分组法将病例分为试验组(n=30)和对照组(n=30);对照组采用常规抗心力衰竭治疗,试验组则将ACEI/ARB类药物替换为沙库巴曲缬沙坦,比较两组患者治疗前后不同时间段血浆N-末端前体B型钠尿肽(NT-proBNP)水平、左室舒张末期内径(LVEDD)、左室射血分数(LVEF)、KCCQ评分,并比较不良反应发生率及再次入院率。 结果 随访显示,试验组患者治疗后6个月的NT-proBNP、LVEDD明显低于对照组,LVEF明显高于对照组,差异有统计学意义(P＜0.05);试验组治疗后4、6个月的KCCQ量表评分高于对照组,差异有统计学意义(P＜0.05);随访6个月,试验组患者的再次入院率低于对照组,差异有统计学意义(P＜0.05),两组不良反应总发生率比较,差异无统计学意义(P＞0.05)。 结论 在急性心肌梗死PCI术后合并慢性心力衰竭患者的治疗中使用沙库巴曲缬沙坦可取得理想的治疗效果,该方法安全有效,值得在临床实践中借鉴并推广。     

沙库巴曲缬沙坦对心肌梗死后不同病程心力衰竭患者的疗效评价

目的:回顾性分析比较心肌梗死（MI）后不同病程心力衰竭（心衰）患者应用沙库巴曲缬沙坦（Sacubitril/Valsartan,LCZ696）的 临床疗效是否存在差异。方法: 收集2018 年1 月1 日—2020 年6 月30 日在天津市第一中心医院心内科住院并首次服用 LCZ696 的MI 后心衰患者共150 例,分为并发心衰组,心衰病程≤2 年组和心衰病程＞2 年组,各50 例,以治疗后3、6、12 个月 为时间节点进行为期1 年的回访,观察心脏超声指标变化和生存情况,并用Cox 回归分析影响疗效的因素。结果:3组患者左心 室射血分数（LVEF）（F=62.111,P＜0.01）和舒张末期内径（LVEDD）（F=38.444,P＜0.01）分别呈逐渐上升和下降趋势,其中在并发 心衰组的变化最显著,组间差异存在统计学意义。3 组间累积无终点事件生存率（90.0%、57.8%、35.3%）有统计学意义（字2= 32.754,P＜0.01）。Cox 回归分析发现长心衰病程患者终点事件发生的风险大（HR=10.407,95%CI:3.957~27.371,P<0.001）。结论: MI 后心衰患者早期启用LCZ696 更有利于改善左室重构,无事件生存率更高。     

前列地尔联合缬沙坦对糖尿病肾病患者氧化应激水平、尿钠排泄及血管内皮活性的影响

目的 探讨前列地尔联合缬沙坦对糖尿病肾病（DN）患者氧化应激水平、尿钠排泄及血管内皮活性的影响。方法 选取武汉市第一医院门诊与病房2021年11月—2022年10月期间收治的DN患者98例。根据治疗方案不同,分为对照组（49例）和试验组（49例）。对照组给予缬沙坦治疗,试验组给予前列地尔联合缬沙坦治疗,比较两组治疗前后氧化应激指标水平[晚期氧化蛋白产物（AOPP）、丙二醛（MDA）、超氧化物歧化酶（SOD）],比较治疗前后两组肾功能情况[肌酐（Scr）、尿素氮（BUN）、24 h尿微量白蛋白定量（MALB）];比较两组治疗前后24 h尿钠及血浆肾素、醛固酮水平情况;比较治疗前后两组血管内皮活性情况[血管内皮生长因子（VEGF）、一氧化氮（NO）、内皮素-1（ET-1）];观察两组临床疗效及不良反应情况。结果 治疗后,两组AOPP、MDA降低,SOD水平上升,且试验组低于对照组（P＜0.05）;治疗后,两组肌酐Scr、BUN、MALB水平降低,试验组更明显（P＜0.05）;治疗后,两组24 h尿钠升高,肾素、醛固酮水平降低,且试验组更明显（P＜0.05）;治疗后,两组VEGF、ET-1水平下降,NO水平升高,且试验组更明显（P＜0.05）,试验组疗效优于对照组（P＜0.05）,两组不良反应无明显差异（P＞0.05）。结论 前列地尔联合缬沙坦治疗DN的疗效满意,可有效降低患者氧化应激水平,提高其尿钠排泄,改善内皮功能,且安全性较高,值得临床推广应用。     

Valsartan and coronary haemodynamics in early post-myocardial infarction in rats

Angiotensin II AT1 receptor blockade (AT1-) has been shown to prolong survival in post-myocardial infarction (MI) heart failure in rats. In this study, we investigated whether an early AT1-induced improvement in coronary vasodilatation reserve (CVR) might be involved in this beneficial effect. Wistar rats with MI were treated daily and orally for 6 weeks with valsartan, 5 (MI-V5) or 50 mg/kg (MI-V50). MI-controls and sham-operated rats (S-controls) received no treatment. Subsequently, systemic and coronary haemodynamics (at baseline and at maximal vasodilatation, CVR fluospheres) were investigated in the conscious state, and cardiac remodelling (hypertrophy and fibrosis) was assessed. As compared to MI-controls. valsartan (5 mg/kg), had no effect on systemic haemodynamics or myocardial hypertrophy and fibrosis development, gave slightly improved basal left and right ventricular coronary flow and resistance values, but decreased left and right CVR values. Valsartan (50 mg/kg), decreased blood pressure (-11%) and left ventricular end diastolic pressure (-32%), limited the development of cardiac hypertrophy (19%) but not that of fibrosis, slightly improved basal left ventricular flow and resistance values but only the right ventricular CVR value was increased. We conclude that in rats with post-MI. an early AT1-induced improvement in coronary haemodynamics is not responsible for the long-term survival prolongation observed. Furthermore. that cardiac hypertrophy was prevented whereas fibrosis was not, suggests that the latter is a pivotal determinant of CVR.